LymphedemaV1, Pmc, Corpus, bibRecord, 000D60

Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015

Identifieur interne : 000D60 ( Pmc/Corpus ); précédent : 000D59; suivant : 000D61

Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015

Auteurs : Capucine Picard ; Waleed Al-Herz ; Aziz Bousfiha ; Jean-Laurent Casanova ; Talal Chatila ; Mary Ellen Conley ; Charlotte Cunningham-Rundles ; Amos Etzioni ; Steven M. Holland ; Christoph Klein ; Shigeaki Nonoyama ; Hans D. Ochs ; Eric Oksenhendler ; Jennifer M. Puck ; Kathleen E. Sullivan ; Mimi L K. Tang ; Jose Luis Franco ; H. Bobby Gaspar

Source :

Journal of Clinical Immunology [ 0271-9142 ] ; 2015.

RBID : PMC:4659841

Abstract

We report the updated classification of primary immunodeficiencies compiled by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS). In the two years since the previous version, 34 new gene defects are reported in this updated version. For each disorder, the key clinical and laboratory features are provided. In this new version we continue to see the increasing overlap between immunodeficiency, as manifested by infection and/or malignancy, and immune dysregulation, as manifested by auto-inflammation, auto-immunity, and/or allergy. There is also an increased number of genetic defects that lead to susceptibility to specific organisms which reflects the finely tuned nature of immune defense systems. This classification is the most up to date catalogue of all known and published primary immunodeficiencies and acts as a current reference of the knowledge of these conditions and is an important aid for the genetic and molecular diagnosis of patients with these rare diseases.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659841

DOI: 10.1007/s10875-015-0201-1
PubMed: 26482257
PubMed Central: 4659841

Links to Exploration step

PMC:4659841

Le document en format XML

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<author><name sortKey="Picard, Capucine" sort="Picard, Capucine" uniqKey="Picard C" first="Capucine" last="Picard">Capucine Picard</name>
<affiliation><nlm:aff id="Aff1">Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Hospital for Sick Children, Paris, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff2">Centre d’étude des déficits immunitaires (CEDI), Hôpital Necker-Enfants Malades, AP-HP, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Al Herz, Waleed" sort="Al Herz, Waleed" uniqKey="Al Herz W" first="Waleed" last="Al-Herz">Waleed Al-Herz</name>
<affiliation><nlm:aff id="Aff3">Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff4">Allergy and Clinical Immunology Unit, Department of Pediatrics, Al-Sabah Hospital, Kuwait City, Kuwait</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bousfiha, Aziz" sort="Bousfiha, Aziz" uniqKey="Bousfiha A" first="Aziz" last="Bousfiha">Aziz Bousfiha</name>
<affiliation><nlm:aff id="Aff5">Clinical Immunology Unit, Casablanca Children’s Hospital, Ibn Rochd Medical School, King Hassan II University, Casablanca, Morocco</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name>
<affiliation><nlm:aff id="Aff1">Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Hospital for Sick Children, Paris, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff6">St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff7">Howard Hughes Medical Institute, New York, NY USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff8">University Paris Descartes, Imagine Institute, Paris, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff9">Pediatric Hematology & Immunology Unit, Necker Hospital for Sick Children, Paris, France</nlm:aff>
</affiliation>
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<author><name sortKey="Chatila, Talal" sort="Chatila, Talal" uniqKey="Chatila T" first="Talal" last="Chatila">Talal Chatila</name>
<affiliation><nlm:aff id="Aff10">Division of Immunology, Children’s Hospital Boston, Boston, MA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Conley, Mary Ellen" sort="Conley, Mary Ellen" uniqKey="Conley M" first="Mary Ellen" last="Conley">Mary Ellen Conley</name>
<affiliation><nlm:aff id="Aff6">St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY USA</nlm:aff>
</affiliation>
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<author><name sortKey="Cunningham Rundles, Charlotte" sort="Cunningham Rundles, Charlotte" uniqKey="Cunningham Rundles C" first="Charlotte" last="Cunningham-Rundles">Charlotte Cunningham-Rundles</name>
<affiliation><nlm:aff id="Aff11">Department of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Etzioni, Amos" sort="Etzioni, Amos" uniqKey="Etzioni A" first="Amos" last="Etzioni">Amos Etzioni</name>
<affiliation><nlm:aff id="Aff12">Meyer Children’s Hospital-Technion, Haifa, Israel</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Holland, Steven M" sort="Holland, Steven M" uniqKey="Holland S" first="Steven M." last="Holland">Steven M. Holland</name>
<affiliation><nlm:aff id="Aff13">Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Klein, Christoph" sort="Klein, Christoph" uniqKey="Klein C" first="Christoph" last="Klein">Christoph Klein</name>
<affiliation><nlm:aff id="Aff14">Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University Munich, Munich, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nonoyama, Shigeaki" sort="Nonoyama, Shigeaki" uniqKey="Nonoyama S" first="Shigeaki" last="Nonoyama">Shigeaki Nonoyama</name>
<affiliation><nlm:aff id="Aff15">Department of Pediatrics, National Defense Medical College, Saitama, Japan</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ochs, Hans D" sort="Ochs, Hans D" uniqKey="Ochs H" first="Hans D." last="Ochs">Hans D. Ochs</name>
<affiliation><nlm:aff id="Aff16">Department of Pediatrics, University of Washington and Seattle Children’s Research Institute, Seattle, WA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Oksenhendler, Eric" sort="Oksenhendler, Eric" uniqKey="Oksenhendler E" first="Eric" last="Oksenhendler">Eric Oksenhendler</name>
<affiliation><nlm:aff id="Aff17">Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff18">Université Paris Diderot, Sorbonne Paris Cité, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Puck, Jennifer M" sort="Puck, Jennifer M" uniqKey="Puck J" first="Jennifer M." last="Puck">Jennifer M. Puck</name>
<affiliation><nlm:aff id="Aff19">Department of Pediatrics, University of California San Francisco and UCSF Benioff Children’s Hospital, San Francisco, CA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sullivan, Kathleen E" sort="Sullivan, Kathleen E" uniqKey="Sullivan K" first="Kathleen E." last="Sullivan">Kathleen E. Sullivan</name>
<affiliation><nlm:aff id="Aff20">Division of Allergy Immunology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tang, Mimi L K" sort="Tang, Mimi L K" uniqKey="Tang M" first="Mimi L K." last="Tang">Mimi L K. Tang</name>
<affiliation><nlm:aff id="Aff21">Murdoch Childrens Research Institute, Melbourne, VIC Australia</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff22">Department of Paediatrics, University of Melbourne, Melbourne, VIC Australia</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff23">Department of Allergy and Immunology, Royal Children’s Hospital, Melbourne, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Franco, Jose Luis" sort="Franco, Jose Luis" uniqKey="Franco J" first="Jose Luis" last="Franco">Jose Luis Franco</name>
<affiliation><nlm:aff id="Aff24">Group of Primary Immunodeficiencies, University of Antioquia, Medellin, Colombia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gaspar, H Bobby" sort="Gaspar, H Bobby" uniqKey="Gaspar H" first="H. Bobby" last="Gaspar">H. Bobby Gaspar</name>
<affiliation><nlm:aff id="Aff25">UCL Institute of Child Health, 30, Guilford Street, London, WC1N 1EH UK</nlm:aff>
</affiliation>
</author>
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<author><name sortKey="Picard, Capucine" sort="Picard, Capucine" uniqKey="Picard C" first="Capucine" last="Picard">Capucine Picard</name>
<affiliation><nlm:aff id="Aff1">Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Hospital for Sick Children, Paris, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff2">Centre d’étude des déficits immunitaires (CEDI), Hôpital Necker-Enfants Malades, AP-HP, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Al Herz, Waleed" sort="Al Herz, Waleed" uniqKey="Al Herz W" first="Waleed" last="Al-Herz">Waleed Al-Herz</name>
<affiliation><nlm:aff id="Aff3">Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff4">Allergy and Clinical Immunology Unit, Department of Pediatrics, Al-Sabah Hospital, Kuwait City, Kuwait</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bousfiha, Aziz" sort="Bousfiha, Aziz" uniqKey="Bousfiha A" first="Aziz" last="Bousfiha">Aziz Bousfiha</name>
<affiliation><nlm:aff id="Aff5">Clinical Immunology Unit, Casablanca Children’s Hospital, Ibn Rochd Medical School, King Hassan II University, Casablanca, Morocco</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name>
<affiliation><nlm:aff id="Aff1">Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Hospital for Sick Children, Paris, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff6">St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff7">Howard Hughes Medical Institute, New York, NY USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff8">University Paris Descartes, Imagine Institute, Paris, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff9">Pediatric Hematology & Immunology Unit, Necker Hospital for Sick Children, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chatila, Talal" sort="Chatila, Talal" uniqKey="Chatila T" first="Talal" last="Chatila">Talal Chatila</name>
<affiliation><nlm:aff id="Aff10">Division of Immunology, Children’s Hospital Boston, Boston, MA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Conley, Mary Ellen" sort="Conley, Mary Ellen" uniqKey="Conley M" first="Mary Ellen" last="Conley">Mary Ellen Conley</name>
<affiliation><nlm:aff id="Aff6">St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cunningham Rundles, Charlotte" sort="Cunningham Rundles, Charlotte" uniqKey="Cunningham Rundles C" first="Charlotte" last="Cunningham-Rundles">Charlotte Cunningham-Rundles</name>
<affiliation><nlm:aff id="Aff11">Department of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Etzioni, Amos" sort="Etzioni, Amos" uniqKey="Etzioni A" first="Amos" last="Etzioni">Amos Etzioni</name>
<affiliation><nlm:aff id="Aff12">Meyer Children’s Hospital-Technion, Haifa, Israel</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Holland, Steven M" sort="Holland, Steven M" uniqKey="Holland S" first="Steven M." last="Holland">Steven M. Holland</name>
<affiliation><nlm:aff id="Aff13">Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Klein, Christoph" sort="Klein, Christoph" uniqKey="Klein C" first="Christoph" last="Klein">Christoph Klein</name>
<affiliation><nlm:aff id="Aff14">Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University Munich, Munich, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nonoyama, Shigeaki" sort="Nonoyama, Shigeaki" uniqKey="Nonoyama S" first="Shigeaki" last="Nonoyama">Shigeaki Nonoyama</name>
<affiliation><nlm:aff id="Aff15">Department of Pediatrics, National Defense Medical College, Saitama, Japan</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ochs, Hans D" sort="Ochs, Hans D" uniqKey="Ochs H" first="Hans D." last="Ochs">Hans D. Ochs</name>
<affiliation><nlm:aff id="Aff16">Department of Pediatrics, University of Washington and Seattle Children’s Research Institute, Seattle, WA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Oksenhendler, Eric" sort="Oksenhendler, Eric" uniqKey="Oksenhendler E" first="Eric" last="Oksenhendler">Eric Oksenhendler</name>
<affiliation><nlm:aff id="Aff17">Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff18">Université Paris Diderot, Sorbonne Paris Cité, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Puck, Jennifer M" sort="Puck, Jennifer M" uniqKey="Puck J" first="Jennifer M." last="Puck">Jennifer M. Puck</name>
<affiliation><nlm:aff id="Aff19">Department of Pediatrics, University of California San Francisco and UCSF Benioff Children’s Hospital, San Francisco, CA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sullivan, Kathleen E" sort="Sullivan, Kathleen E" uniqKey="Sullivan K" first="Kathleen E." last="Sullivan">Kathleen E. Sullivan</name>
<affiliation><nlm:aff id="Aff20">Division of Allergy Immunology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tang, Mimi L K" sort="Tang, Mimi L K" uniqKey="Tang M" first="Mimi L K." last="Tang">Mimi L K. Tang</name>
<affiliation><nlm:aff id="Aff21">Murdoch Childrens Research Institute, Melbourne, VIC Australia</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff22">Department of Paediatrics, University of Melbourne, Melbourne, VIC Australia</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff23">Department of Allergy and Immunology, Royal Children’s Hospital, Melbourne, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Franco, Jose Luis" sort="Franco, Jose Luis" uniqKey="Franco J" first="Jose Luis" last="Franco">Jose Luis Franco</name>
<affiliation><nlm:aff id="Aff24">Group of Primary Immunodeficiencies, University of Antioquia, Medellin, Colombia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gaspar, H Bobby" sort="Gaspar, H Bobby" uniqKey="Gaspar H" first="H. Bobby" last="Gaspar">H. Bobby Gaspar</name>
<affiliation><nlm:aff id="Aff25">UCL Institute of Child Health, 30, Guilford Street, London, WC1N 1EH UK</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Journal of Clinical Immunology</title>
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<front><div type="abstract" xml:lang="en"><p>We report the updated classification of primary immunodeficiencies compiled by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS). In the two years since the previous version, 34 new gene defects are reported in this updated version. For each disorder, the key clinical and laboratory features are provided. In this new version we continue to see the increasing overlap between immunodeficiency, as manifested by infection and/or malignancy, and immune dysregulation, as manifested by auto-inflammation, auto-immunity, and/or allergy. There is also an increased number of genetic defects that lead to susceptibility to specific organisms which reflects the finely tuned nature of immune defense systems. This classification is the most up to date catalogue of all known and published primary immunodeficiencies and acts as a current reference of the knowledge of these conditions and is an important aid for the genetic and molecular diagnosis of patients with these rare diseases.</p>
</div>
</front>
</TEI>
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  <front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Immunol</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Clin. Immunol</journal-id>
<journal-title-group><journal-title>Journal of Clinical Immunology</journal-title>
</journal-title-group>
<issn pub-type="ppub">0271-9142</issn>
<issn pub-type="epub">1573-2592</issn>
<publisher><publisher-name>Springer US</publisher-name>
<publisher-loc>New York</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26482257</article-id>
<article-id pub-id-type="pmc">4659841</article-id>
<article-id pub-id-type="publisher-id">201</article-id>
<article-id pub-id-type="doi">10.1007/s10875-015-0201-1</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Original Research</subject>
</subj-group>
</article-categories>
<title-group><article-title>Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Picard</surname>
<given-names>Capucine</given-names>
</name>
<xref ref-type="aff" rid="Aff1"></xref>
<xref ref-type="aff" rid="Aff2"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Al-Herz</surname>
<given-names>Waleed</given-names>
</name>
<xref ref-type="aff" rid="Aff3"></xref>
<xref ref-type="aff" rid="Aff4"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bousfiha</surname>
<given-names>Aziz</given-names>
</name>
<xref ref-type="aff" rid="Aff5"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Casanova</surname>
<given-names>Jean-Laurent</given-names>
</name>
<xref ref-type="aff" rid="Aff1"></xref>
<xref ref-type="aff" rid="Aff6"></xref>
<xref ref-type="aff" rid="Aff7"></xref>
<xref ref-type="aff" rid="Aff8"></xref>
<xref ref-type="aff" rid="Aff9"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chatila</surname>
<given-names>Talal</given-names>
</name>
<xref ref-type="aff" rid="Aff10"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Conley</surname>
<given-names>Mary Ellen</given-names>
</name>
<xref ref-type="aff" rid="Aff6"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cunningham-Rundles</surname>
<given-names>Charlotte</given-names>
</name>
<xref ref-type="aff" rid="Aff11"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Etzioni</surname>
<given-names>Amos</given-names>
</name>
<xref ref-type="aff" rid="Aff12"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Holland</surname>
<given-names>Steven M.</given-names>
</name>
<xref ref-type="aff" rid="Aff13"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Klein</surname>
<given-names>Christoph</given-names>
</name>
<xref ref-type="aff" rid="Aff14"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nonoyama</surname>
<given-names>Shigeaki</given-names>
</name>
<xref ref-type="aff" rid="Aff15"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ochs</surname>
<given-names>Hans D.</given-names>
</name>
<xref ref-type="aff" rid="Aff16"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Oksenhendler</surname>
<given-names>Eric</given-names>
</name>
<xref ref-type="aff" rid="Aff17"></xref>
<xref ref-type="aff" rid="Aff18"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Puck</surname>
<given-names>Jennifer M.</given-names>
</name>
<xref ref-type="aff" rid="Aff19"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sullivan</surname>
<given-names>Kathleen E.</given-names>
</name>
<xref ref-type="aff" rid="Aff20"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tang</surname>
<given-names>Mimi L K.</given-names>
</name>
<xref ref-type="aff" rid="Aff21"></xref>
<xref ref-type="aff" rid="Aff22"></xref>
<xref ref-type="aff" rid="Aff23"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Franco</surname>
<given-names>Jose Luis</given-names>
</name>
<xref ref-type="aff" rid="Aff24"></xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Gaspar</surname>
<given-names>H. Bobby</given-names>
</name>
<address><phone>+44 2079052319</phone>
<email>h.gaspar@ucl.ac.uk</email>
</address>
<xref ref-type="aff" rid="Aff25"></xref>
</contrib>
<aff id="Aff1"><label></label>
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Hospital for Sick Children, Paris, France</aff>
<aff id="Aff2"><label></label>
Centre d’étude des déficits immunitaires (CEDI), Hôpital Necker-Enfants Malades, AP-HP, Paris, France</aff>
<aff id="Aff3"><label></label>
Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait</aff>
<aff id="Aff4"><label></label>
Allergy and Clinical Immunology Unit, Department of Pediatrics, Al-Sabah Hospital, Kuwait City, Kuwait</aff>
<aff id="Aff5"><label></label>
Clinical Immunology Unit, Casablanca Children’s Hospital, Ibn Rochd Medical School, King Hassan II University, Casablanca, Morocco</aff>
<aff id="Aff6"><label></label>
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY USA</aff>
<aff id="Aff7"><label></label>
Howard Hughes Medical Institute, New York, NY USA</aff>
<aff id="Aff8"><label></label>
University Paris Descartes, Imagine Institute, Paris, France</aff>
<aff id="Aff9"><label></label>
Pediatric Hematology & Immunology Unit, Necker Hospital for Sick Children, Paris, France</aff>
<aff id="Aff10"><label></label>
Division of Immunology, Children’s Hospital Boston, Boston, MA USA</aff>
<aff id="Aff11"><label></label>
Department of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY USA</aff>
<aff id="Aff12"><label></label>
Meyer Children’s Hospital-Technion, Haifa, Israel</aff>
<aff id="Aff13"><label></label>
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD USA</aff>
<aff id="Aff14"><label></label>
Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University Munich, Munich, Germany</aff>
<aff id="Aff15"><label></label>
Department of Pediatrics, National Defense Medical College, Saitama, Japan</aff>
<aff id="Aff16"><label></label>
Department of Pediatrics, University of Washington and Seattle Children’s Research Institute, Seattle, WA USA</aff>
<aff id="Aff17"><label></label>
Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France</aff>
<aff id="Aff18"><label></label>
Université Paris Diderot, Sorbonne Paris Cité, Paris, France</aff>
<aff id="Aff19"><label></label>
Department of Pediatrics, University of California San Francisco and UCSF Benioff Children’s Hospital, San Francisco, CA USA</aff>
<aff id="Aff20"><label></label>
Division of Allergy Immunology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA USA</aff>
<aff id="Aff21"><label></label>
Murdoch Childrens Research Institute, Melbourne, VIC Australia</aff>
<aff id="Aff22"><label></label>
Department of Paediatrics, University of Melbourne, Melbourne, VIC Australia</aff>
<aff id="Aff23"><label></label>
Department of Allergy and Immunology, Royal Children’s Hospital, Melbourne, Australia</aff>
<aff id="Aff24"><label></label>
Group of Primary Immunodeficiencies, University of Antioquia, Medellin, Colombia</aff>
<aff id="Aff25"><label></label>
UCL Institute of Child Health, 30, Guilford Street, London, WC1N 1EH UK</aff>
</contrib-group>
<pub-date pub-type="epub"><day>19</day>
<month>10</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>19</day>
<month>10</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="ppub"><year>2015</year>
</pub-date>
<volume>35</volume>
<issue>8</issue>
<fpage>696</fpage>
<lpage>726</lpage>
<history><date date-type="received"><day>20</day>
<month>7</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>20</day>
<month>9</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s) 2015</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.</license-p>
</license>
</permissions>
<abstract id="Abs1"><p>We report the updated classification of primary immunodeficiencies compiled by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS). In the two years since the previous version, 34 new gene defects are reported in this updated version. For each disorder, the key clinical and laboratory features are provided. In this new version we continue to see the increasing overlap between immunodeficiency, as manifested by infection and/or malignancy, and immune dysregulation, as manifested by auto-inflammation, auto-immunity, and/or allergy. There is also an increased number of genetic defects that lead to susceptibility to specific organisms which reflects the finely tuned nature of immune defense systems. This classification is the most up to date catalogue of all known and published primary immunodeficiencies and acts as a current reference of the knowledge of these conditions and is an important aid for the genetic and molecular diagnosis of patients with these rare diseases.</p>
</abstract>
<kwd-group xml:lang="en"><title>Keywords</title>
<kwd>Primary immunodeficiencies</kwd>
<kwd>classification</kwd>
<kwd>genetic defects</kwd>
</kwd-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© Springer Science+Business Media New York 2015</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<body><sec id="Sec1" sec-type="introduction"><title>Background</title>
<p>The International Union of Immunological Societies (IUIS) Expert Committee on Primary Immunodeficiency met in London on the 14th and 15th March 2015 to update the classification of human primary immunodeficiencies (PIDs). This report represents the most current and complete catalogue of known PIDs. It serves as a reference for these conditions and provides a framework to help in the diagnostic approach to patients suspected to have PID.</p>
<p>As in previous reports, we have classified the conditions into major groups of PIDs and these are now represented in 9 different tables (Tables <xref rid="Tab1" ref-type="table">1</xref>
, <xref rid="Tab2" ref-type="table">2</xref>
, <xref rid="Tab3" ref-type="table">3</xref>
, <xref rid="Tab4" ref-type="table">4</xref>
, <xref rid="Tab5" ref-type="table">5</xref>
, <xref rid="Tab6" ref-type="table">6</xref>
, <xref rid="Tab7" ref-type="table">7</xref>
,<xref rid="Tab8" ref-type="table">8</xref>
 and <xref rid="Tab9" ref-type="table">9</xref>
). In each table, we list the condition, its genetic defect if known and the major immunological and in some conditions the non-immunological abnormalities associated with the disease. This year we have added the gene OMIM number as well as the phenotype OMIM number for ease of reference.<table-wrap id="Tab1"><label>Table 1</label>
<caption><p>Immunodeficiencies affecting cellular and humoral immunity</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th>Disease</th>
<th>Genetic defect/Presumed pathogenesis<break></break>
Gene OMIM</th>
<th>Inheritance</th>
<th>Circulating T cells</th>
<th>Circulating B cells</th>
<th>Serum Ig</th>
<th>Associated Features</th>
<th>Phenotype<break></break>
OMIM number</th>
</tr>
</thead>
<tbody><tr><td colspan="8">T<sup>−</sup>
B<sup>+</sup>
 Severe Combined Immunodeficiency (SCID)</td>
</tr>
<tr><td> γc deficiency</td>
<td>Mutation of <italic>IL2RG</italic>
<break></break>
Defect in γ chain of receptors for IL-2, -4, -7, -9, -15, -21<break></break>
308380</td>
<td>XL</td>
<td>Markedly decreased</td>
<td>Normal or increased</td>
<td>Decreased</td>
<td>Markedly decreased NK cells;</td>
<td>300400</td>
</tr>
<tr><td> JAK3 deficiency</td>
<td>Mutation of <italic>JAK3</italic>
<break></break>
Defect in Janus activating kinase 3<break></break>
600173</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Normal or increased</td>
<td>Decreased</td>
<td>Markedly decreased NK cells;</td>
<td>600802</td>
</tr>
<tr><td> IL7Rα deficiency</td>
<td>Mutation of <italic>IL7RA</italic>
<break></break>
Defect in IL-7 receptor α chain<break></break>
146661</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Normal or increased</td>
<td>Decreased</td>
<td>Normal NK cells</td>
<td>608971</td>
</tr>
<tr><td> CD45 deficiency</td>
<td>Mutation of <italic>PTPRC</italic>
<break></break>
Defect in CD45<break></break>
151460</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Normal</td>
<td>Decreased</td>
<td>Normal γ/δ T cells</td>
<td>608971</td>
</tr>
<tr><td> CD3δ deficiency</td>
<td>Mutation of <italic>CD3D</italic>
<break></break>
Defect in CD3δ, chain of T cell antigen receptor complex<break></break>
186790,</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Normal</td>
<td>Decreased</td>
<td>Normal NK cells<break></break>
No γ/δ T cells</td>
<td>615617</td>
</tr>
<tr><td> CD3ε deficiency</td>
<td>Mutation of <italic>CD3E</italic>
<break></break>
Defect in CD3ε chain of T cell antigen receptor complex<break></break>
186830,</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Normal</td>
<td>Decreased</td>
<td>Normal NK cells<break></break>
No γ/δ T cells</td>
<td>615615</td>
</tr>
<tr><td> CD3ζ deficiency</td>
<td>Mutation of <italic>CD3Z</italic>
<break></break>
Defect in CD3ζ chain of T cell antigen receptor complex<break></break>
186780</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Normal</td>
<td>Decreased</td>
<td>Normal NK cells<break></break>
No γ/δ T cells</td>
<td>610163</td>
</tr>
<tr><td> Coronin-1A deficiency</td>
<td>Mutation of <italic>CORO1A</italic>
 Defective thymic egress of T cells and defective T cell locomotion<break></break>
605000</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Normal</td>
<td>Decreased</td>
<td>Detectable thymus<break></break>
EBV-associated B-cell lymphoproliferation</td>
<td>615401</td>
</tr>
<tr><td colspan="8">T<sup>−</sup>
B<sup>−</sup>
 SCID</td>
</tr>
<tr><td colspan="8"> DNA recombination defects (for additional DNA repair defects see Table <xref rid="Tab2" ref-type="table">2</xref>
)</td>
</tr>
<tr><td> RAG 1 deficiency</td>
<td>Mutation of <italic>RAG1</italic>
<break></break>
Defective VDJ recombination; defect of recombinase activating gene (RAG) 1<break></break>
179615</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Markedly decreased</td>
<td>Decreased</td>
<td></td>
<td>601457</td>
</tr>
<tr><td> RAG 2 deficiency</td>
<td>Mutation of <italic>RAG2</italic>
<break></break>
Defective VDJ recombination; defect of recombinase activating gene (RAG) 2<break></break>
179616</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Markedly decreased</td>
<td>Decreased</td>
<td></td>
<td>601457</td>
</tr>
<tr><td> DCLRE1C (Artemis) deficiency</td>
<td>Mutation of <italic>ARTEMIS</italic>
<break></break>
Defective VDJ recombination; defect in Artemis DNA recombinase-repair protein<break></break>
605988</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Markedly decreased</td>
<td>Decreased</td>
<td>Radiation sensitivity</td>
<td>602450</td>
</tr>
<tr><td> DNA PKcs deficiency</td>
<td>Mutation of <italic>PRKDC</italic>
 Defective VDJ recombination; defect in DNA PKcs<break></break>
Recombinase repair protein<break></break>
600899</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Markedly decreased</td>
<td>variable</td>
<td>Radiation sensitivity, microcephaly and developmental defects<break></break>
Autoimmunity and granuloma</td>
<td>615966</td>
</tr>
<tr><td>  Cernunnos/XLF deficiency</td>
<td>Mutation of <italic>Cernunnos</italic>
 Defective VDJ recombination; defect in Cernunnos<break></break>
611290</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Markedly decreased</td>
<td>Decreased</td>
<td>Radiation sensitivity, microcephaly and developmental defects</td>
<td>611291</td>
</tr>
<tr><td> DNA ligase IV deficiency</td>
<td>Mutation of <italic>LIG4</italic>
 Defective VDJ recombination; defect in DNA ligase IV<break></break>
601837</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Markedly decreased</td>
<td>Decreased</td>
<td>Radiation sensitivity, microcephaly and developmental defects</td>
<td>606593</td>
</tr>
<tr><td> Reticular dysgenesis, AK2 deficiency</td>
<td>Mutation of <italic>AK2</italic>
<break></break>
Defective maturation of lymphoid and myeloid cells (stem cell defect)<break></break>
Defect in mitochondrial adenylate kinase 2.<break></break>
103020</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Decreased or normal</td>
<td>Decreased</td>
<td>Granulocytopenia and deafness</td>
<td>267500</td>
</tr>
<tr><td> Adenosine deaminase (ADA) deficiency</td>
<td>Mutation of <italic>ADA</italic>
<break></break>
Absent ADA activity, elevated lymphotoxic metabolites (dATP, S-adenosyl homocysteine)<break></break>
608958</td>
<td>AR</td>
<td>Absent from birth (null mutations) or progressive decrease</td>
<td>Absent from birth of progressive decrease</td>
<td>Progressive decrease</td>
<td>Decreased NK cells, often with costochondral junction flaring, neurological features, hearing impairment, lung and liver manifestations; partial ADA deficiency may lead to delayed or milder presentation</td>
<td>102700</td>
</tr>
<tr><td colspan="8"> Combined immunodeficiencies generally less profound than severe combined immunodeficiency</td>
</tr>
<tr><td> DOCK2 deficiency</td>
<td>Mutations in <italic>DOCK2</italic>
 required for RAC1 activation, actin polymerization, T-cell proliferation, chemokine-induced lymphocyte migration and NK-cell degranulation<break></break>
603122</td>
<td>AR</td>
<td>Decreased. Poor response to PHA. Low TRECs</td>
<td>Normal</td>
<td>Decreased/ Normal. Poor antibody responses</td>
<td>Normal NK numbers, but defective function. Impaired interferon responses in hematopoietic and non-hematopoietic cells</td>
<td>616433</td>
</tr>
<tr><td> CD40 ligand deficiency</td>
<td>Mutation of <italic>CD40LG</italic>
 Defects in CD40 ligand (CD40L; also called TNFSF5 or CD154) cause defective isotype switching and impaired dendritic cell signaling<break></break>
300386</td>
<td>XL</td>
<td>Normal; may progressively decrease</td>
<td>sIgM<sup>+</sup>
 and sIgD<sup>+</sup>
 B cells present, other surface isotype positive B cells absent</td>
<td>IgM increased or normal, other isotypes decreased</td>
<td>Neutropenia, thrombocytopenia; hemolytic anemia, biliary tract and liver disease, opportunistic infections</td>
<td>308230</td>
</tr>
<tr><td> CD40 deficiency</td>
<td>Mutation of <italic>CD40 (</italic>
also called TNFRSF5)<break></break>
Defects in CD40 cause defective isotype switching and impaired dendritic cell signaling<break></break>
109535</td>
<td>AR</td>
<td>Normal</td>
<td>IgM<sup>+</sup>
 and IgD<sup>+</sup>
 B cells present, other isotypes absent</td>
<td>IgM increased or normal, other isotypes decreased</td>
<td>Neutropenia, gastrointestinal and liver/biliary tract disease, opportunistic infections</td>
<td>606843</td>
</tr>
<tr><td> ICOS deficiency</td>
<td>Mutations in <italic>ICOS;</italic>
 a co-stimulatory molecule expressed on T cells<break></break>
604558</td>
<td>AR</td>
<td>Normal</td>
<td>Normal</td>
<td>Low</td>
<td>Recurrent infections; autoimmunity, gastroenteritis, may have granulomas</td>
<td>607594</td>
</tr>
<tr><td> CD3γ deficiency</td>
<td>Mutation of <italic>CD3G.</italic>
 Defect in CD3γ component of the T cell antigen receptor complex<break></break>
186740</td>
<td>AR</td>
<td>Normal, but reduced TCR expression</td>
<td>Normal</td>
<td>Normal</td>
<td></td>
<td>615607</td>
</tr>
<tr><td> CD8 deficiency</td>
<td>Mutation of <italic>CD8A.</italic>
 Defects of CD8 α chain, important for maturation and function of CD8 T cells<break></break>
186910</td>
<td>AR</td>
<td>Absent CD8, normal CD4 cells</td>
<td>Normal</td>
<td>Normal</td>
<td></td>
<td></td>
</tr>
<tr><td> ZAP-70 deficiency</td>
<td>Mutation in ZAP70 intracellular signaling kinase, acts downstream of TCR<break></break>
176947</td>
<td>AR</td>
<td>Decreased CD8, normal CD4 cells</td>
<td>Normal</td>
<td>Normal</td>
<td>Autoimmunity in some cases</td>
<td>269840</td>
</tr>
<tr><td> MHC class I deficiency</td>
<td>Mutations in <italic>TAP1</italic>
, gene, causing MHC class I non-expression<break></break>
170260</td>
<td>AR</td>
<td>Decreased CD8, normal CD4 cells;<break></break>
absent MHC I expression on lymphocytes</td>
<td>Normal</td>
<td>Normal</td>
<td>Vasculitis; pyoderma gangrenosum</td>
<td>604571</td>
</tr>
<tr><td> MHC class I deficiency</td>
<td>Mutations in <italic>TAP2</italic>
, gene, causing MHC class I non-expression<break></break>
170261</td>
<td>AR</td>
<td>Decreased CD8, normal CD4 cells;<break></break>
absent MHC I expression on lymphocytes</td>
<td>Normal</td>
<td>Normal</td>
<td>Vasculitis; pyoderma gangrenosum</td>
<td>604571</td>
</tr>
<tr><td> MHC class I deficiency</td>
<td>Mutations in <italic>TAPBP</italic>
 (tapasin) gene, causing MHC class I non-expression<break></break>
601962</td>
<td>AR</td>
<td>Decreased CD8, normal CD4 cells;<break></break>
absent MHC I expression on lymphocytes</td>
<td>Normal</td>
<td>Normal</td>
<td>Vasculitis; pyoderma gangrenosum</td>
<td>604571</td>
</tr>
<tr><td> MHC class I deficiency</td>
<td>Mutations in <italic>B2M</italic>
 gene, causing MHC class I non-expression<break></break>
109700</td>
<td>AR</td>
<td>Decreased CD8, normal CD4 cells;<break></break>
absent MHC I expression on lymphocytes</td>
<td>Normal</td>
<td>Normal</td>
<td>Sinopulmonary infections, cutaneous granuloma, hypoproteinemia. Absent expression of β2m associated proteins like MHC-I, CD1a, and CD1b, CD1c on β2m-deficient cells</td>
<td>not yet assigned</td>
</tr>
<tr><td> MHC class II deficiency group A</td>
<td>Mutation in transcription factors for MHC class II proteins (<italic>CIITA</italic>
 gene)<break></break>
600005</td>
<td>AR</td>
<td>Decreased CD4 cells<break></break>
Absent MHC II expression on lymphocytes</td>
<td>Normal</td>
<td>Normal or decreased</td>
<td>Failure to thrive, diarrhea, respiratory tract infections liver/biliary tract disease</td>
<td>209920</td>
</tr>
<tr><td> MHC class II deficiency<break></break>
group B</td>
<td>Mutation in transcription factors for MHC class II proteins <italic>RFXANK</italic>
 gene<break></break>
603200</td>
<td>AR</td>
<td>Decreased CD4 cells<break></break>
Absent MHC II expression on lymphocytes</td>
<td>Normal</td>
<td>Normal or decreased</td>
<td>Failure to thrive, diarrhea, respiratory tract infections liver/biliary tract disease</td>
<td>209920</td>
</tr>
<tr><td> MHC class II deficiency group C</td>
<td>Mutation in transcription factors for MHC class II proteins <italic>RFX5</italic>
, gene)<break></break>
601863</td>
<td>AR</td>
<td>Decreased CD4 cells<break></break>
Absent MHC II expression on lymphocytes</td>
<td>Normal</td>
<td>Normal or decreased</td>
<td>Failure to thrive, diarrhea, respiratory tract infections liver/biliary tract disease</td>
<td>209920</td>
</tr>
<tr><td> MHC class II deficiency<break></break>
group D</td>
<td>Mutation in transcription factors for MHC class II proteins (<italic>RFXAP</italic>
 gene<break></break>
601861</td>
<td>AR</td>
<td>Decreased CD4 cells<break></break>
Absent MHC II expression on lymphocytes</td>
<td>Normal</td>
<td>Normal or decreased</td>
<td>Failure to thrive, diarrhea, respiratory tract infections liver/biliary tract disease</td>
<td>209920</td>
</tr>
<tr><td> ITK deficiency</td>
<td>Mutations in <italic>ITK</italic>
 encoding IL-2 inducible T cell kinase required for TCR-mediated activation<break></break>
186973</td>
<td>AR</td>
<td>Progressive decrease</td>
<td>Normal</td>
<td>Normal or decreased</td>
<td>EBV associated B cell lymphop-roliferation, lymphoma<break></break>
Normal or decreased IgG</td>
<td>613011</td>
</tr>
<tr><td> MAGT1 deficiency</td>
<td>Mutations in <italic>MAGT1</italic>
, Impaired Mg<sup>++</sup>
 flux leading to impaired TCR signaling 300715</td>
<td>XL</td>
<td>Decreased CD4 cells reduced numbers of RTE, impaired T-cell proliferation in response to CD3</td>
<td>Normal</td>
<td>Normal</td>
<td>EBV infection, lymphoma; viral infections, respiratory and GI infections,</td>
<td>300853</td>
</tr>
<tr><td> DOCK8 deficiency</td>
<td>Mutations in <italic>DOCK8</italic>
 encoding a dedicator of cytokinesis regulator of intracellular actin reorganisation<break></break>
611432</td>
<td>AR</td>
<td>Decreased; Impaired T lymphocyte proliferation; Treg deficiency and poor function</td>
<td>Decreased; low CD27+ memory B cells</td>
<td>Low IgM, increased IgE</td>
<td>Decreased NK cells with impaired function, hypereosinophilia, recurrent infections; severe atopy, extensive cutaneous viral and staphylococcal infections, susceptibility to cancer. Defects in peripheral B tolerance.</td>
<td>243700</td>
</tr>
<tr><td> RhoH deficiency</td>
<td>Mutations in <italic>RHOH</italic>
 – an atypical Rho GTPase transducing signals downstream of various membrane receptors<break></break>
602037</td>
<td>AR</td>
<td>Normal<break></break>
low naïve T cells and RTE, restricted T cell repertoire and impaired T cells proliferation in response to CD3 stimulation.</td>
<td>Normal</td>
<td>Normal</td>
<td>HPV infection, lymphoma, lung granulomas, molluscum contagiosum,</td>
<td>not yet assigned</td>
</tr>
<tr><td> MST1 deficiency</td>
<td>Mutations in <italic>STK4</italic>
 – a serine/threonine kinase<break></break>
604965</td>
<td>AR</td>
<td>Decreased increased proportion of terminal differentiated effector memory cells (TEMRA), low naïve T cells, restricted T cell repertoire in the TEMRA population and impaired T cells proliferation</td>
<td>Decreased</td>
<td>High</td>
<td>Recurrent bacterial, viral, and candidal infections; intermittent neutropenia; EBV-driven lymphoproliferation; lymphoma; Congenital heart disease, autoimmune cytopenias; HPV infection.</td>
<td>614868</td>
</tr>
<tr><td>  TCRα deficiency</td>
<td>Mutations in <italic>TRAC</italic>
 – essential component of the T cell receptor<break></break>
186880</td>
<td>AR</td>
<td>Normal All CD3 T cells expressed TCRγδ (or may be better to say: TCRαβ T-cell deficiency), impaired T cells proliferation</td>
<td>Normal</td>
<td>Normal</td>
<td>Recurrent viral, bacterial and fungal infections, immune dysregulation autoimmunity, and diarrhea.</td>
<td>615387</td>
</tr>
<tr><td> LCK deficiency</td>
<td>Defects in <italic>LCK</italic>
 – a proximal tyrosine kinase that interacts with TCR<break></break>
153390</td>
<td>AR</td>
<td>Normal total numbers but CD4+ T-cell lymphopenia, low Treg numbers, restricted T cell repertoire and impaired TCR signaling</td>
<td>Normal</td>
<td>Normal IgG and IgA and increased IgM</td>
<td>Diarrhea, recurrent infections, immune dysregulation autoimmunity,</td>
<td>615758</td>
</tr>
<tr><td> MALT1 deficiency</td>
<td>Mutations in <italic>MALT1</italic>
 –<break></break>
a caspase-like cysteine protease that is essential for nuclear factor-kappa-B activation<break></break>
604860</td>
<td>AR</td>
<td>Normal number but impaired T cells proliferation</td>
<td>Normal</td>
<td>Normal<break></break>
Impaired antibody response</td>
<td>Bacterial, fungal and viral infections</td>
<td>615468</td>
</tr>
<tr><td> CARD11 deficiency</td>
<td>Defects in <italic>CARD11</italic>
 – acts as a scaffold for NF-КB activity in the adaptive immune response<break></break>
607210</td>
<td>AR</td>
<td>Normal predominance of naive T-lymphocyte, impaired T cells proliferation</td>
<td>Normal predominance of transitional B lymphocytes,</td>
<td>Absent/low</td>
<td>Pneumocystis jirovicii pneumonia, bacterial infections,</td>
<td>615206</td>
</tr>
<tr><td> BCL10 deficiency</td>
<td>Mutations in <italic>BCL10</italic>
 which encodes the B cell CLL / lymphoma 10 protein that forms a heterotrimer with Malt1 and CARD family adaptors and plays a role in NF-kB signaling<break></break>
603517</td>
<td>AR</td>
<td>Normal numbers, low memory T and Tregs, decreased proliferation to antigen and anti-CD3</td>
<td>Normal number; decreased memory and switched B cells</td>
<td>Low</td>
<td>Recurrent bacterial and viral infections, candidiasis, gastroenteritis</td>
<td>616098</td>
</tr>
<tr><td> IL-21 deficiency</td>
<td>Mutation in <italic>IL21</italic>
<break></break>
605384</td>
<td>AR</td>
<td>Normal number.<break></break>
Normal/low function</td>
<td>Low</td>
<td>IgG deficiency</td>
<td>Severe early onset colitis</td>
<td>615767</td>
</tr>
<tr><td> IL-21R deficiency</td>
<td>Defects in <italic>IL21R</italic>
 – together with common gamma chain binds IL-21<break></break>
605383</td>
<td>AR</td>
<td>Abnormal T cell cytokine production; Abnormal T cell proliferation to specific stimuli</td>
<td>Normal</td>
<td>Normal but impaired specific responses</td>
<td>Suspectibility to cryptoporidia and pneumocystis and cholangitis</td>
<td>615207</td>
</tr>
<tr><td> OX40 deficiency</td>
<td>Defects in <italic>OX40 (TNFRSF4</italic>
) encoding a co-stimulatory molecule expressed on activated T cells<break></break>
600315</td>
<td>AR</td>
<td>Normal T cell numbers; decreased antigen specific memory CD4+ cells</td>
<td>Normal B cell numbers; reduced frequency of memory B cells</td>
<td>Normal</td>
<td>Kaposi’s sarcoma; impaired immunity to HHV8</td>
<td>615593</td>
</tr>
<tr><td> IKBKB deficiency</td>
<td>Defects in <italic>IKBKB</italic>
, encoding IkB 2 kinase 2, a component of the NF-kB pathway<break></break>
603258</td>
<td>AR</td>
<td>Normal total T cells; absent regulatory and γδ T cells; impaired TCR activation</td>
<td>Normal B cell numbers; impaired BCR activation;</td>
<td>Decreased</td>
<td>Recurrent bacterial, viral and fungal infections; clinical phenotype of SCID</td>
<td>615592</td>
</tr>
<tr><td> LRBA deficiency</td>
<td>Mutations in <italic>LRBA</italic>
 (lipopolysaccharide responsive beige-like anchor protein)<break></break>
606453</td>
<td>AR</td>
<td>Normal or decreased CD4 numbers; T cell dysregulation</td>
<td>Low or normal numbers of B cells</td>
<td>Reduced I IgG and IgA in most</td>
<td>Recurrent infections, inflammatory bowel disease, autoimmunity; EBV infections</td>
<td>614700</td>
</tr>
<tr><td> CD27 deficiency</td>
<td>Mutations in <italic>CD27</italic>
 (<italic>TNFRSF7</italic>
) encoding TNF-R member superfamily required for generation and long-term maintenance of T cell immunity<break></break>
186711</td>
<td>AR</td>
<td>Normal</td>
<td>No memory B cells</td>
<td>Hypogamma-globulinaemia following EBV infection</td>
<td>Clinical and immunologic features triggered by EBV infection, HLH<break></break>
Aplastic anaemia, Lymphoma,<break></break>
hypogammaglobulinemia,<break></break>
Low iNKT cells</td>
<td>615122</td>
</tr>
<tr><td> NIK deficiency</td>
<td>Mutation in <italic>MAP3K14</italic>
, encoding NIK (NF-kB-inducing kinase)<break></break>
604655</td>
<td>AR</td>
<td>Normal number; impaired proliferation in response to antigen stimulation. Polycloncal Vβ repertoires</td>
<td>Decreased total peripheral B cell and switched memory B cells</td>
<td>Hypogamma-globulinaemia</td>
<td>Recurrent bacterial, viral and Cryptosporidium infections. Low NK cell number and defective NK cell activation</td>
<td>Not yet assigned</td>
</tr>
<tr><td> CTPS1 deficiency</td>
<td>Mutation in <italic>CTPS1</italic>
, encoding CTP synthase 1, essential for lymphocyte proliferation<break></break>
123860</td>
<td>AR</td>
<td>Normal or decreased number<break></break>
Normal or decreased proliferation</td>
<td>Normal/low number</td>
<td>Normal/high IgG</td>
<td>Recurrent/chronic viral infections specially EBV and VZV, bacterial infections, EBV-driven<break></break>
B-cell non-Hodgkin lymphoma</td>
<td>615897</td>
</tr>
<tr><td> Omenn syndrome</td>
<td>Hypomorphic mutations in <italic>RAG1, RAG2</italic>
, <italic>Artemis, IL7RA</italic>
, <italic>RMRP, ADA, DNA Ligase IV, IL2RG</italic>
, <italic>AK2</italic>
, or associated with DiGeorge syndrome; some cases have no defined gene mutation</td>
<td></td>
<td>Present; restricted T cell repertoire and impaired function</td>
<td>Normal or decreased</td>
<td>Decreased, except for increased IgE</td>
<td>Erythroderma, eosinophilia, adenopathies, hepatosplenomegaly</td>
<td>603554</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>Total no. of genes in Table <xref rid="Tab1" ref-type="table">1</xref>
: 49</p>
<p>New genes added: <italic>DOCK2, B2M, IL21</italic>
, <italic>MAP3K14, CTPS1</italic>
</p>
<p>Notes: Infants with SCID who have maternal T cell engraftment may have allogeneic T cells present even in normal numbers, but that do not function normally; these cells may cause autoimmune cytopenias or graft versus host disease. Hypomorphic mutations in several of the genes that when affected by null mutations cause SCID may result in Omenn syndrome (OS), or “leaky” SCID or a less profound combined immunodeficiency or CID phenotype. Both OS and leaky SCID can be associated with >300 autologous T cells/uL of peripheral blood and reduced rather than absent proliferative responses; Individuals with partially defective, or leaky, mutations are generally more mildly affected compared with those with typical SCID caused by null mutations. A spectrum of clinical findings including typical SCID, OS, leaky SCID, CID, granulomas with T lymphopenia, autoimmunity and CD4+ T lymphopenia can be found in an allelic series of <italic>RAG1</italic>
 and other SCID associated genes. RAC2 deficiency is a disorder of leukocyte motility and is reported in Table <xref rid="Tab5" ref-type="table">5</xref>
; however, one patient with RAC2 deficiency had absent T cell receptor excision circles (TRECs) by newborn screening, though T cell numbers and mitogen responses were not impaired. For additional syndromic conditions with T cell lymphopenia, such as DNA repair defects, cartilage hair hypoplasia, IKAROS deficiency and NEMO syndrome, see Tables <xref rid="Tab2" ref-type="table">2</xref>
 and <xref rid="Tab6" ref-type="table">6</xref>
; however, it should be noted that individuals with the most severe manifestations of these disorders could have clinical signs and symptoms of SCID</p>
<p>UNC119 deficiency has been removed from this version of the classification tables, as the <italic>UNC119</italic>
 variant reported previously has been identified as a polymorphism in unaffected individuals (Gorska MM, Alam R. A mutation in the human Uncoordinated 119 gene impairs TCR signaling and is associated with CD4 lymphopenia. <italic>Blood</italic>
. 2012 Feb 9;119(6):1399–406. doi: 10.1182/blood-2011-04-350686. Epub 2011 Dec 19). See Erratum (Blood. 2014 Jan 16;123(3):457)</p>
<p><italic>XL</italic>
 X-linked inheritance, <italic>AR</italic>
 autosomal recessive inheritance, <italic>AD</italic>
 autosomal dominant inheritance, <italic>SCID</italic>
 severe combined immune deficiency, <italic>EBV</italic>
 epstein barr virus, <italic>Ca</italic>
<sup><italic>++</italic>
</sup>
 calcium, <italic>MHC</italic>
 major histocompatibility complex, <italic>RTE</italic>
 recent thymic emigrants, <italic>HPV</italic>
 human papillomavirus</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="Tab2"><label>Table 2</label>
<caption><p>Combined immunodeficiencies with associated or syndromic features</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th>Disease</th>
<th>Genetic defect/Presumed pathogenesis<break></break>
OMIM number gene locus</th>
<th>Inheritance</th>
<th>Circulating T cells</th>
<th>Circulating B cells</th>
<th>Serum Ig</th>
<th>Associated features</th>
<th>OMIM number<break></break>
Phenotype</th>
</tr>
</thead>
<tbody><tr><td colspan="8">1. Congenital thrombocytopenia</td>
</tr>
<tr><td> Wiskott-Aldrich syndrome (WAS)</td>
<td>Mutations in <italic>WAS</italic>
; cytoskeletal and immunologic synapse defect affecting haematopoietic stem cell derivatives<break></break>
301000</td>
<td>XL</td>
<td>Progressive decrease, Abnormal lymphocyte responses to anti-CD3</td>
<td>Normal numbers</td>
<td>Decreased IgM: antibody to polysaccharides particularly decreased; often increased IgA and IgE</td>
<td>Thrombocytopenia with small platelets; eczema; lymphoma; autoimmune disease; IgA nephropathy; bacterial and viral infections. XL thrombocytopenia is a mild form of WAS, and XL neutropenia is caused by missense mutations in the GTPase binding domain of WASP</td>
<td>300392</td>
</tr>
<tr><td> WIP deficiency</td>
<td>Mutations in <italic>WIPF1</italic>
; cytoskeletal and immunologic synapse defect affecting haematopoietic stem cell derivatives 602357</td>
<td>AR</td>
<td>Reduced, Defective lymphocyte responses to anti-CD3</td>
<td>Low</td>
<td>Normal, except for increased IgE</td>
<td>Recurrent infections; eczema; thrombocytopenia. WAS-<italic>like</italic>
 phenotype.</td>
<td>614493</td>
</tr>
<tr><td colspan="8">2. DNA repair defects (other than those in Table <xref rid="Tab1" ref-type="table">1</xref>
)</td>
</tr>
<tr><td> Ataxia-telangiectasia</td>
<td>Mutations in <italic>ATM</italic>
; disorder of cell cycle check-point and DNA double- strand break repair<break></break>
607585</td>
<td>AR</td>
<td>Progressive decrease, abnormal proliferation to mitogens</td>
<td>Normal</td>
<td>Often decreased IgA, IgE and IgG subclasses; increased IgM monomers; antibodies variably decreased</td>
<td>Ataxia; telangiectasia; pulmonary infections; lymphoreticular and other malignancies; increased alpha fetoprotein and increased radiosensitivity; chromosomal instability</td>
<td>208900</td>
</tr>
<tr><td> Nijmegen breakage syndrome</td>
<td>Hypomorphic mutations in <italic>NBS1</italic>
<break></break>
(<italic>Nibrin</italic>
); disorder of cell cycle checkpoint and DNA double- strand break repair<break></break>
602667</td>
<td>AR</td>
<td>Progressive decrease</td>
<td>Variably reduced</td>
<td>Often decreased IgA, IgE and IgG subclasses; increased IgM; antibodies variably decreased</td>
<td>Microcephaly; bird-like face; lymphomas; solid tumors; increased radiosensitivity; chromosomal instability</td>
<td>251260</td>
</tr>
<tr><td> Bloom syndrome</td>
<td>Mutations in <italic>BLM (RECQL3</italic>
); encoding DNA helicase RecQ protein-like 3 helicase<break></break>
604610</td>
<td>AR</td>
<td>Normal</td>
<td>Normal</td>
<td>Reduced</td>
<td>Short stature; bird like face; sun-sensitive erythema; marrow failure; leukemia; lymphoma; chromosomal instability</td>
<td>210900</td>
</tr>
<tr><td> Immunodeficiency with centromeric instability and facial anomalies (ICF1)</td>
<td>Mutations in DNA methyltransferase<italic>DNMT3B</italic>
 (ICF1) resulting in defective DNA methylation 602900;</td>
<td>AR</td>
<td>Decreased or normal; responses to PHA may be decreased</td>
<td>Decreased or normal</td>
<td>Hypogammaglobulinemia; variable antibody deficiency</td>
<td>Facial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16; no DNA breaks</td>
<td>242860</td>
</tr>
<tr><td> Immunodeficiency with centromeric instability and facial anomalies (ICF2)</td>
<td>Mutations in <italic>ZBTB24</italic>
 (ICF2)<break></break>
614064</td>
<td>AR</td>
<td>Decreased or normal;<break></break>
Responses to PHA may be decreased</td>
<td>Decreased or normal</td>
<td>Hypogammaglobulinemia; variable antibody deficiency</td>
<td>Facial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16;</td>
<td>614069</td>
</tr>
<tr><td> PMS2 deficiency</td>
<td>Mutations in <italic>PMS2</italic>
, resulting in Class Switch recombination deficiency due to impaired mismatch repair<break></break>
600259</td>
<td>AR</td>
<td>Normal</td>
<td>Reduced B cells, switched and non-switched</td>
<td>Low IgG and IgA, elevated IgM, abnormal antibody responses</td>
<td>Recurrent infections; café-au-lait spots; lymphoma, colorectal carcinoma, brain tumor</td>
<td>276300</td>
</tr>
<tr><td> RNF168 deficiency</td>
<td>Mutations in <italic>RNF168</italic>
, resulting in defective DNA double-strand break repair (RIDDLE syndrome) 612688</td>
<td>AR</td>
<td>Normal</td>
<td>Normal</td>
<td>Low IgG, IgM, or low IgA</td>
<td>Short stature; mild defect of motor control to ataxia; normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly; increased radiosensitivity</td>
<td>611943</td>
</tr>
<tr><td> MCM4 deficiency</td>
<td>Mutations in <italic>MCM4</italic>
 (minichromosome maintenance complex component 4) gene involved in DNA replication and repair<break></break>
602638</td>
<td>AR</td>
<td>Normal</td>
<td>Normal</td>
<td>Normal</td>
<td>Viral infections (EBV, HSV, VZV)<break></break>
Adrenal failure<break></break>
Short stature<break></break>
Low NK cells</td>
<td>609981</td>
</tr>
<tr><td colspan="8">3. Thymic defects with additional congenital anomalies</td>
</tr>
<tr><td> DiGeorge syndrome*</td>
<td>Contiguous gene deletion in chromosome 22q11.2 or mutation of a gene within this deletion region, <italic>TBX1</italic>
, encoding a transcription factor critical for development of thymus and adjacent embryonic structures<break></break>
602054</td>
<td><italic>De novo</italic>
 haplo-insufficiency (majority) or AD; phenocopies may have other as yet undefined genetic lesions</td>
<td>Decreased or normal; 5 % have <1500 CD3 T cells/uL in neonatal period</td>
<td>Normal</td>
<td>Normal or decreased</td>
<td>Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability and other abnormalities; often with 3 Mb interstitial deletion in 22q11.2 (or rarely with intragenic mutation of <italic>TBX1</italic>
, deletion in 10p)</td>
<td>188400</td>
</tr>
<tr><td> CHARGE syndrome due to CHD7 defects</td>
<td>Variable defects of the thymus and associated T cell abnormalities, often due to deletions or mutations in transcription regulator <italic>CHD7</italic>
,<break></break>
608892</td>
<td><italic>De novo</italic>
 haplo-insufficiency (majority) or AD</td>
<td>Decreased or normal; response to PHA may be decreased</td>
<td>Normal</td>
<td>Normal or decreased</td>
<td>Coloboma, heart anomaly, choanal atresia, mental retardation, genital and ear anomalies; some are SCID-like and have low TRECs</td>
<td>214800</td>
</tr>
<tr><td> CHARGE syndrome due to SEMA3E defects</td>
<td>Variable defects of the thymus and associated T cell abnormalities, often due to deletions or mutations in transcription regulator, or semaphorin <italic>SEMA3E</italic>
 608166</td>
<td><italic>De novo</italic>
 haplo-insufficiency (majority) or AD</td>
<td>Decreased or normal; response to PHA may be decreased</td>
<td>Normal</td>
<td>Normal or decreased</td>
<td>Coloboma, heart anomaly, choanal atresia, mental retardation, genital and ear anomalies; some are SCID-like and have low TRECs</td>
<td>214800</td>
</tr>
<tr><td> Winged helix deficiency (nude)<break></break>
 AAB: syndromic SCID</td>
<td>Defects in forkhead box N1 transcription factor encoded by <italic>FOXN1</italic>
<break></break>
600838</td>
<td>AR</td>
<td>Markedly decreased</td>
<td>Normal</td>
<td>Decreased</td>
<td>Alopecia; nail dystropphy; severe infections abnormal thymic epithelium, impaired T cell maturation</td>
<td>601705</td>
</tr>
<tr><td colspan="8">4. Immune-osseous dysplasias</td>
</tr>
<tr><td> Cartilage hair hypoplasia</td>
<td>Mutations in <italic>RMRP</italic>
 (RNase MRP RNA) Involved in processing of mitochondrial RNA and cell cycle control<break></break>
157660</td>
<td>AR</td>
<td>Varies from severely decreased (SCID) to normal; impaired lymphocyte proliferation</td>
<td>Normal</td>
<td>Normal or reduced antibodies variably decreased</td>
<td>Short-limbed dwarfism with metaphysealdysostosis, sparse hair, bone marrow failure, autoimmunity, susceptibility to lymphoma and other cancers, impaired spermatogenesis, neuronal dysplasia of the intestine</td>
<td>250250</td>
</tr>
<tr><td> Schimke<break></break>
 Immunoosseous<break></break>
 Dysplasia</td>
<td>Mutations in <italic>SMARCAL1;</italic>
 involved in chromatin remodeling<break></break>
606622</td>
<td>AR</td>
<td>Decreased</td>
<td>Normal</td>
<td>Normal</td>
<td>Short stature, spondiloepiphyseal dysplasia, intrauterine growth retardation, nephropathy; bacterial, viral, fungal infections; may present as SCID; bone marrow failure</td>
<td>242900</td>
</tr>
<tr><td colspan="8">5. Hyper-IgE syndromes (HIES)</td>
</tr>
<tr><td> AD-HIES (Job or Buckley Syndrome)</td>
<td>Dominant-negative heterozygous mutations in signal transducer and activator of transcription <italic>STAT3</italic>
<break></break>
102582</td>
<td>AD<break></break>
Often <italic>de novo</italic>
 mutation</td>
<td>Normal overall Th-17 and T-follicular helper cells decreased</td>
<td>Normal; reduced switched and non-switched memory B cells; BAFF expression increased</td>
<td>Elevated IgE; specific antibody production decreased</td>
<td>Distinctive facial features (broad nasal bridge), bacterial infections (boils and pulmonary abscesses, pneumatoceles) due to <italic>S. aureus</italic>
, aspergillus, <italic>Pneumocystis jirovecii</italic>
; eczema, mucocutaneous candidiasis, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retention of primary teeth, aneurysm formation</td>
<td>147060</td>
</tr>
<tr><td> Comel-Netherton syndrome</td>
<td>Mutations in <italic>SPINK5</italic>
 resulting in lack of the serine protease inhibitor LEKTI, expressed in epithelial cells<break></break>
605010</td>
<td>AR</td>
<td>Normal</td>
<td>Switched and non-switched B cells are reduced</td>
<td>Elevated IgE and IgA<break></break>
Antibody variably decreased</td>
<td>Congenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive</td>
<td>256500</td>
</tr>
<tr><td> PGM3 deficiency</td>
<td>Mutations inphosphoglycomutase 3 (<italic>PGM3)</italic>
 associated with a glycosylationand atopy<break></break>
172100</td>
<td>AR</td>
<td>CD8 and CD4 T cells may be decreased</td>
<td>Reduced B and memory B cells</td>
<td>Normal or elevated Ig’s, elevated IgE; eosinophilia</td>
<td>Severe atopy, autoimmunity, bacterial and viral infections, cognitive impairment, hypomyelination</td>
<td>615816</td>
</tr>
<tr><td colspan="8">6. Dyskeratosis congenita (DKC) with bone marrow failure and dysfunctional telomere maintenance</td>
</tr>
<tr><td> XL-DKC due to Dyskerin deficiency</td>
<td>Mutations in <italic>DKC1</italic>
 encoding dyskerin<break></break>
300126</td>
<td>XL</td>
<td>Progressive decrease</td>
<td>Progressive decrease</td>
<td>Variable hypogammag-lobulinemia</td>
<td>Intrauterine growth retardation, microcephaly, nail dystrophy, recurrent infections, digestive tract involvement, pancytopenia, reduced number and function of NK cells. A severe phenotype with developmental delay and cerebellar hypoplasia is known as Hoyeraal-Hreidarsson Syndrome (HHS)</td>
<td>305000</td>
</tr>
<tr><td> AR-DKC due to nucleolar protein family A member 2 (NHP2) deficiency</td>
<td>Mutations in <italic>NOLA2</italic>
 (<italic>NHP2</italic>
),<break></break>
component of the H/ACA ribonucleo-protein complex<break></break>
606470</td>
<td>AR</td>
<td>Decreased</td>
<td>Variable</td>
<td>Variable</td>
<td>Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, hypoplastic/dysplastic nails</td>
<td>613987</td>
</tr>
<tr><td> AR-DKC due to nucleolar protein family A member 3 (NHP3) or NOP10 deficiency</td>
<td>Mutation in <italic>NOLA3</italic>
 (<italic>NOP10, PCFT</italic>
), a component of the H/ACA ribonucleo-protein complex<break></break>
606471</td>
<td>AR</td>
<td>Decreased</td>
<td>Variable</td>
<td>Variable</td>
<td>Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, hypoplastic/dysplastic nails</td>
<td>224230</td>
</tr>
<tr><td> AR-DKC due to regulator of telomere elongation (RTEL1) deficiency</td>
<td>Mutation in <italic>RTEL1</italic>
 encoding regulator of telomere elongation helicase 1 (RTEL1)<break></break>
608833</td>
<td>AD or AR</td>
<td>Decreased</td>
<td>Variable</td>
<td>Variable</td>
<td>Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, hypoplastic/dysplastic nails. May present as HHS</td>
<td>615190</td>
</tr>
<tr><td> AD-DKC due to TERC deficiency</td>
<td>Mutation in <italic>TERC</italic>
 encoding telomerase RNA component<break></break>
602322</td>
<td>AD</td>
<td>Variable</td>
<td>Variable</td>
<td>Variable</td>
<td>Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the oral mucosa, palmar hyperkeratosis, anemia, pancytopenia. May present as HHS</td>
<td>127550</td>
</tr>
<tr><td> AD-DKC due to TERT deficiency</td>
<td>Mutation in <italic>TERT</italic>
 encoding telomerase reverse transcriptase 187270</td>
<td>AD or AR</td>
<td>Variable</td>
<td>Variable</td>
<td>Variable</td>
<td>Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the oral mucosa, palmar hyperkeratosis, anemia, pancytopenia. AD version is milder than the AR version which can resemble HHS</td>
<td>613989</td>
</tr>
<tr><td> AD-DKC due to TINF2 deficiency</td>
<td>Mutation in <italic>TINF2</italic>
 encoding telomerase interacting factor 2 604319</td>
<td>AD</td>
<td>Variable</td>
<td>Variable</td>
<td>Variable</td>
<td>Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the oral mucosa, palmar hyperkeratosis, anemia, pancytopenia. May present as HHS</td>
<td>613990</td>
</tr>
<tr><td> AD/AR -DKC due to TPP1 deficiency</td>
<td>Mutation in adrenocortical dysplasia homolog (ACD) encoding TPP1 affecting the TELpatch domain resulting in failure to recruit telomerase to telomers<break></break>
609377</td>
<td>AD/AR</td>
<td>Variable</td>
<td>Variable</td>
<td>Variable</td>
<td>Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis leukoplakia of the oralmucosa, carcinoma, leukemia palmar hyperkeratosis, anemia, pancytopenia. May present as HHS</td>
<td></td>
</tr>
<tr><td> AR-DKC due to DCLRE1B deficiency</td>
<td>Mutation in DCLRE1B/ SNM1/APOLLO: DNA CROSS-LINK REPAIR PROTEIN 1B<break></break>
609683</td>
<td>AR</td>
<td></td>
<td></td>
<td></td>
<td>dyskeratosis congenita and Hoyeraal-Hreidarsson (HH) syndrome</td>
<td>616353</td>
</tr>
<tr><td> AR-DKC due to PARN deficiency</td>
<td>Mutation in PARN, POLYADENYLATE-SPECIFIC RIBONUCLEASE<break></break>
604212</td>
<td>AR</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>616353</td>
</tr>
<tr><td colspan="8">7. Defects of Vitamin B12 and Folate metabolism</td>
</tr>
<tr><td> Transcobalamin 2 (TCN2) deficiency</td>
<td>Mutation in <italic>TCN2</italic>
; encoding a transporter of cobalamin into blood cells<break></break>
613441</td>
<td>AR</td>
<td>Normal</td>
<td>Variable</td>
<td>Decreased</td>
<td>Megaloblastic anaemia, pancytopaenia, if untreated for prolonged periods results in mental retardation</td>
<td>275350</td>
</tr>
<tr><td> SLC46A1/PCFT deficiency causing hereditary folate malabsorbtion</td>
<td>Mutation in <italic>SLC46A1</italic>
, encoding a proton coupled folate transporter</td>
<td>AR</td>
<td>Variable numbers and activation profile</td>
<td>Variable</td>
<td>Decreased</td>
<td>Megaloblastic anaemia, failure to thrive, if untreated for prolonged periods results in mental retardation</td>
<td>229050<break></break>
611672</td>
</tr>
<tr><td> Methylene-tetrahydrofolate dehydrogenase 1 (MTHFD1) deficiency</td>
<td>Mutations in enzyme encoded by <italic>MTHFD</italic>
, essential <underline>for</underline>
 processing single-carbon folate derivatives</td>
<td>AR</td>
<td>Low</td>
<td>Low</td>
<td>Decreased</td>
<td>Megaloblastic anaemia, failure to thrive, neutropenia, seizures, mental retardation</td>
<td>601634<break></break>
172460</td>
</tr>
<tr><td colspan="8">8. Anhidrotic ectodermaldysplasia with immunodeficiency (EDA-ID)</td>
</tr>
<tr><td> (EDA-ID. NEMO /IKBKG deficiency</td>
<td>Mutations of <italic>NEMO</italic>
 (<italic>IKBKG</italic>
), a modulator of NF-κB activation<break></break>
Defects in <italic>IKBKG</italic>
, encoding NEMO, a component of the NF-κB pathway<break></break>
Mutations of NEMO (<italic>IKBKG</italic>
), a modulator of NF-κB activation<break></break>
300248</td>
<td>XL</td>
<td>Normal or decreased; poor CR activation function</td>
<td>Normal<break></break>
Low B memory B cells</td>
<td>Decreased; poor specific antibody responses, absent antibody to polysaccharide antigens</td>
<td>anhidrotic ectodermal dysplasia + specific antibody deficiency (lack of Ab response to polysac-charides) + various infections (mycobacteria and pyogens)<break></break>
Various infections (bacteria, mycobacteria, viruses and fungi); colitis, EDA (not in all patients); conical teeth, variable defects of skin pigmentation, monocyte dysfunction</td>
<td>300291, 300584, 300301<break></break>
300640</td>
</tr>
<tr><td> EDA-ID IKBA gain of function mutation</td>
<td>Gain of function mutation in <italic>IKBA (NFKIAB)</italic>
, encoding IκBα, a component of the NF-κB pathway<break></break>
Gain-of-function mutation of <italic>IKBA</italic>
, resulting in impaired activation of NF-κB<break></break>
164008</td>
<td>AD</td>
<td>Normal total T cells;; impaired TCR activation</td>
<td>Normal B cell numbers; impaired BCR activation;</td>
<td>Decreased; poor specific antibody responses, absent antibody to polysaccharide antigens</td>
<td>Various infections (bacteria, mycobacteria, viruses and fungi); colitis, EDA (not in all patients); variable defects of skin, hair and teeth, T cell and monocyte dysfunction<break></break>
Anhidrotic ectodermal dysplasia + T cell defect + various infections: Recurrent bacterial, viral and fungal infections;</td>
<td>612132</td>
</tr>
<tr><td colspan="8">9. Calcium channel defects</td>
</tr>
<tr><td> ORAI-I deficiency</td>
<td>Mutation in <italic>ORAI1</italic>
, a Ca<sup>++</sup>
 release-activated channel (CRAC) modulatory component<break></break>
610277</td>
<td>AR</td>
<td>Normal; defective TCR mediated activation</td>
<td>Normal</td>
<td>Normal</td>
<td>Autoimmunity, anhydrotic ectodermic dysplasia, non-progressive myopathy</td>
<td>612782</td>
</tr>
<tr><td> STIM1 deficiency</td>
<td>Mutations in <italic>STIM1</italic>
, a stromal interaction molecule 1<break></break>
605921</td>
<td>AR</td>
<td>Normal; defective TCR mediated activation</td>
<td>Normal</td>
<td>Normal</td>
<td>Autoimmunity, anhydrotic ectodermal dysplasia, non-progressive myopathy</td>
<td>612783</td>
</tr>
<tr><td colspan="8">10. Other defects</td>
</tr>
<tr><td> Hepatic veno-occlusive disease with immunodeficiency (VODI)</td>
<td>Mutations in nuclear body protein encoded by <italic>SP110</italic>
<break></break>
604457</td>
<td>AR</td>
<td>Normal (decreased memory T cells)</td>
<td>Normal (decreased memory B cells)</td>
<td>Decreased IgG, IgA, IgM; absent germinal centers and tissue plasma cells</td>
<td>Hepatic veno-occlusive disease; Susceptibility to <italic>Pneumocystis jiroveci</italic>
 pneumonia, CMV, candida; thrombocytopenia; hepatosplenomegaly; cerebrospinal leukodystropy</td>
<td>235550</td>
</tr>
<tr><td> Facial dysmorphism, immunodeficiency, livedo, short stature (FILS) syndrome</td>
<td>Mutation in <italic>POLE1</italic>
; Defective DNA replication<break></break>
174762</td>
<td>AR</td>
<td>Low naïve T cells; decreased T cell proliferation</td>
<td>Low memory B cells</td>
<td>Decreased IgM and IgG; Lack of antibodies to polysaccharide antigens</td>
<td>Mild facial dysmorphism (malar hypoplasia, high forehead), livedo, short stature; recurrent upper and lower respiratory tract infections, recurrent pulmonary infections and recurrent meningitis</td>
<td>615139</td>
</tr>
<tr><td> Immunodeficiency with multiple intestinal atresias</td>
<td>Mutation in <italic>TTC7A</italic>
 (tetratricopeptide repeat (TPR) domain 7A) protein, of unkown function<break></break>
609332</td>
<td>AR</td>
<td>Variable, but sometimes absent</td>
<td>Normal</td>
<td>Decreased</td>
<td>Multiple intestinal atresias, often with intrauterine polyhydramnios and early demise; some with SCID phenotype</td>
<td>243150</td>
</tr>
<tr><td> Vici syndrome due to EPG5 deficiency</td>
<td>Mutations in <italic>EPG5</italic>
 encoding ectopic P-granules autophagy protein 5, involved in the formation of autolysosomes required for autophagy</td>
<td>AR</td>
<td>Profound depletion of CD4+ cells</td>
<td>Defective</td>
<td>Decreased (particularly IgG2)</td>
<td>Agenesis of the corpus callosum, cataracts, cardiomyopathy, skin hypopigmentation, cleft lip/palate, recurrent infections, chronic mucocutaneous candidiasis</td>
<td>242840<break></break>
615068</td>
</tr>
<tr><td> Purine nucleoside phosphorylase (PNP) deficiency</td>
<td>Mutation of <italic>PNP</italic>
 leading to absent PNP, T cell and neurologic defects from elevated toxic metabolites, especially dGTP<break></break>
164050</td>
<td>AR</td>
<td>Progressive decrease</td>
<td>Normal</td>
<td>Normal or decreased</td>
<td>Autoimmune haemolytic anemia, neurological impairment</td>
<td>613179</td>
</tr>
<tr><td> HOIL1 deficiency</td>
<td>Mutation of <italic>HOIL1/RBCK1</italic>
, encoding a component of the linear ubiquitination chain assembly complex LUBAC, resulting in impaired activation of NF-κB<break></break>
610924</td>
<td>AR</td>
<td>Normal numbers,</td>
<td>Normal, but decreased memory B cells</td>
<td>Poor antibody production to polysaccharide antigens</td>
<td>Bacterial infections (pyogens), autoinflammation. amylopectinosis</td>
<td>615895</td>
</tr>
<tr><td> HOIP deficiency</td>
<td>Mutation of <italic>HOIP1 (/RNF31)</italic>
, encoding a component of the linear ubiquitination chain assembly complex LUBAC, resulting in impaired activation of NF-κB<break></break>
612487</td>
<td>AR</td>
<td>Normal numbers</td>
<td>Normal, but decreased memory B cells</td>
<td>decreased</td>
<td>Bacterial infections (pyogens), autoinflammation. Amylopectinosis, Lymphangiectasia</td>
<td>Not yet assigned</td>
</tr>
<tr><td> Hennekam-lymphangiectasia-lymphedema syndrome</td>
<td>Mutation of <italic>CCBE1</italic>
: (COLLAGEN AND CALCIUM-BINDING EGF DOMAIN-CONTAINING PROTEIN1)<break></break>
612753</td>
<td>AR</td>
<td>Low/variable</td>
<td>Low/variable</td>
<td>decreased</td>
<td>Lymphangiactasia and lymphedema with facial abnormalities and other dysmorphic features</td>
<td>235510</td>
</tr>
<tr><td> STAT5b deficiency</td>
<td>Mutations in <italic>STAT5B</italic>
 signal transducer and transcription factor, essential for normal signaling from IL-2 and 15, key growth factors for T and NK cells, as well as other cytokines<break></break>
604260</td>
<td>AR</td>
<td>Modestly decreased</td>
<td>Normal</td>
<td>Normal</td>
<td>Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity</td>
<td>245590</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>Total no. of genes in Table <xref rid="Tab2" ref-type="table">2</xref>
: 45</p>
<p>New genes added: <italic>TPP1, DCLRE1B, PARN, CCBE1, HOIP1, EPG5</italic>
</p>
<p>Notes: T and B cell number and function in these disorders exhibit a wide range of abnormality; the most severely affected cases meet diagnostic criteria for SCID or leaky SCID and require immune system restoring therapy such as allogeneic hematopoietic cell transplantation</p>
<p>* Although TBX1 deletions are emphasized, data are lacking that demonstrate that isolated TBX1 haploinsufficiency (affecting solely the gene and none of the surrounding 22q11.2 region) explicitly causes T cell or immunologic deficiency in humans</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="Tab3"><label>Table 3</label>
<caption><p>Predominantly antibody deficiencies</p>
</caption>
<table frame="hsides" rules="groups"><tbody><tr><td>Disease</td>
<td>Genetic defect/Presumed pathogenesis<break></break>
Gene OMIM</td>
<td>Inheritance</td>
<td>Serum Ig</td>
<td>Associated features</td>
<td>Phenotype<break></break>
OMIM number</td>
</tr>
<tr><td colspan="6">1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells</td>
</tr>
<tr><td> BTK deficiency</td>
<td>Mutations in <italic>BTK</italic>
, a cytoplasmic tyrosine kinase activated by crosslinking of the BCR<break></break>
300300</td>
<td>XL</td>
<td>All isotypes decreased in majority of patients; some patients have detectable immunoglobulins</td>
<td>Severe bacterial infections; normal numbers of pro-B cells</td>
<td>300755</td>
</tr>
<tr><td> μ heavy chain deficiency</td>
<td>Mutations in μ heavy chain (<italic>IGHM</italic>
); essential component of the pre-BCR<break></break>
147020</td>
<td>AR</td>
<td>All isotypes decreased</td>
<td>Severe bacterial infections; normal numbers of pro-B cells</td>
<td>601495</td>
</tr>
<tr><td> λ5 deficiency</td>
<td>Mutations in λ5 (<italic>IGLL1</italic>
); part of the surrogate light chain in the pre-BCR<break></break>
146770</td>
<td>AR</td>
<td>All isotypes decreased</td>
<td>Severe bacterial infections; normal numbers of pro-B cells</td>
<td>613500</td>
</tr>
<tr><td> Igα deficiency</td>
<td>Mutations in Igα (<italic>CD79A</italic>
); part of the pre-BCR and BCR 112205</td>
<td>AR</td>
<td>All isotypes decreased</td>
<td>Severe bacterial infections; normal numbers of pro-B cells</td>
<td>112205<break></break>
613501</td>
</tr>
<tr><td> Igβ deficiency</td>
<td>Mutations in Igb (<italic>CD79B</italic>
); part of the pre-BCR and BCR<break></break>
147245</td>
<td>AR</td>
<td>All isotypes decreased</td>
<td>Severe bacterial infections; normal numbers of pro-B cells</td>
<td>612692</td>
</tr>
<tr><td> BLNK deficiency</td>
<td>Mutations in <italic>BLNK</italic>
; a scaffold protein that binds to BTK 604615</td>
<td>AR</td>
<td>All isotypes decreased</td>
<td>Severe bacterial infections; normal numbers of pro-B cells</td>
<td>613502</td>
</tr>
<tr><td> PI3KR1 deficiency</td>
<td>Mutations in <italic>PIK3R1;</italic>
 a kinase involved in signal transduction in multiple cell types. Complete loss of PI3K p85-alpha resulting in complete loss of B cell development<break></break>
171833</td>
<td>AR</td>
<td>All isotypes decreased</td>
<td>Severe bacterial infections; decreased or absent pro-B cells</td>
<td>615214</td>
</tr>
<tr><td> E47 transcription factor deficiency</td>
<td>Mutations in <italic>TCF3</italic>
; a transcription factor required for control of B cell development<break></break>
147141</td>
<td>AD</td>
<td>All isotypes decreased</td>
<td>Recurrent bacterial infections</td>
<td>Not yet assigned</td>
</tr>
<tr><td> Thymoma with immunodeficiency</td>
<td>Unknown</td>
<td>None</td>
<td>One or more isotypes may be decreased</td>
<td>Bacterial and opportunistic infections; autoimmunity; decreased number of pro-B cells</td>
<td></td>
</tr>
<tr><td> Disease</td>
<td>Genetic defect/Presumed pathogenesis</td>
<td>Inheritance</td>
<td>Serum Ig</td>
<td>Associated features</td>
<td>OMIM number</td>
</tr>
<tr><td colspan="6">2. Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low number of B cells</td>
</tr>
<tr><td> Common variable immuno-deficiency disorders</td>
<td>Unknown</td>
<td>Variable</td>
<td>Low IgG and IgA and/or IgM</td>
<td>Clinical phenotypes vary: most have recurrent infections, some have polyclonal lymphoproliferation, autoimmune cytopenias and/or granulomatous disease</td>
<td></td>
</tr>
<tr><td> CD19 deficiency</td>
<td>Mutations in <italic>CD19</italic>
; transmembrane protein that amplifies signal through BCR 107265</td>
<td>AR</td>
<td>Low IgG and IgA and/or IgM</td>
<td>Recurrent infections; May have glomerulonephritis</td>
<td>613493</td>
</tr>
<tr><td> CD81 deficiency</td>
<td>Mutations in <italic>CD81</italic>
; transmembrane protein that amplifies signal through BCR 186845</td>
<td>AR</td>
<td>Low IgG, low or normal IgA and IgM</td>
<td>Recurrent infections; May have glomerulonephritis</td>
<td>613496</td>
</tr>
<tr><td> CD20 deficiency</td>
<td>Mutations in <italic>CD20;</italic>
 a B cell surface receptor involved in B cell development and plasma cell differentiation<break></break>
112210</td>
<td>AR</td>
<td>Low IgG, normal or elevated IgM and IgA</td>
<td>Recurrent infections</td>
<td>613495</td>
</tr>
<tr><td> CD21 deficiency</td>
<td>Mutations in <italic>CD21;</italic>
 also known as complement receptor 2 and forms part of the CD19 complex<break></break>
120650</td>
<td>AR</td>
<td>Low IgG; impaired anti-pneumococcal response</td>
<td>Recurrent infections</td>
<td>614699</td>
</tr>
<tr><td> TACI deficiency</td>
<td>Mutations in <italic>TNFRSF13B</italic>
 (TACI); a TNF receptor family member found on B cells and is a receptor for BAFF and APRIL<break></break>
604907</td>
<td>AD or AR or complex</td>
<td>Low IgG and IgA and/or IgM</td>
<td>Variable clinical expression</td>
<td>240500</td>
</tr>
<tr><td> BAFF receptor deficiency</td>
<td>Mutations in <italic>TNFRSF13C</italic>
 (BAFF-R); a TNF receptor family member found on B cells and is a receptor for BAFF<break></break>
606269</td>
<td>AR</td>
<td>Low IgG and IgM;</td>
<td>Variable clinical expression</td>
<td>613494</td>
</tr>
<tr><td> TWEAK deficiency</td>
<td>Mutations in a cytokine <italic>TWEAK (TNFSF12);</italic>
 TNF-related weak inducer of apoptosis<break></break>
602695</td>
<td>AD</td>
<td>Low IgM and A; lack of anti-pneumococcal antibody</td>
<td>Pneumonia, bacterial infections, warts; thrombocytopenia. neutropenia</td>
<td>not yet assigned</td>
</tr>
<tr><td> NFKB2 deficiency</td>
<td>Mutations in <italic>NFKB2</italic>
; an essential component of the noncanonical NF-κB pathway</td>
<td>AD</td>
<td>Low IgG and IgA and IgM; very low B cells in some</td>
<td>Recurrent infections; adrenal insufficiency; ACTH deficiency; alopecia</td>
<td>615577</td>
</tr>
<tr><td> MOGS deficiency</td>
<td>Mutation in mannosyl-oligosaccharide glucosidase<break></break>
601336</td>
<td>AR</td>
<td>Severe hypogammaglobulinemia;</td>
<td>Bacterial and viral infections; severe neurologic disease; also contains glycosylation type IIb (CDG-IIb),</td>
<td>606056</td>
</tr>
<tr><td> 
<italic>TRNT1 deficiency</italic>
</td>
<td>Mutation in <italic>TRNT1 a</italic>
 template-independent RNA polymerase required for the maturation of cytosolic and mitochondrial transfer RNAs (tRNAs) 612907</td>
<td>AR</td>
<td>B cell deficiency and hypogammaglobulinemia</td>
<td>congenital sideroblastic anemia; deafness; developmental delay</td>
<td>616084</td>
</tr>
<tr><td> TTC37 deficiency</td>
<td><italic>Mutation in TTC37</italic>
 gene<break></break>
614589</td>
<td>AR</td>
<td>Poor antibody response to pneumococcal vaccine</td>
<td>Recurrent bacterial and viral infections; Abnormal hair findings: trichorrhexis nodosa</td>
<td>222470</td>
</tr>
<tr><td colspan="6">3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells</td>
</tr>
<tr><td> AID deficiency</td>
<td>Mutations in <italic>AICDA</italic>
 gene<break></break>
605257</td>
<td>AR</td>
<td>IgG and IgA decreased; IgM increased</td>
<td>Bacterial infections; enlarged lymph nodes and germinal centers</td>
<td>605258</td>
</tr>
<tr><td> UNG deficiency</td>
<td>Mutations in <italic>UNG</italic>
<break></break>
191525</td>
<td>AR</td>
<td>IgG and IgA decreased; IgM increased</td>
<td>Enlarged lymph nodes and germinal centers</td>
<td>608106</td>
</tr>
<tr><td> INO80</td>
<td>INO80 chromatin remodeling complex; mild DNA repair defect 610169</td>
<td>AR</td>
<td>IgG and IgA decreased; IgM increased</td>
<td>Severe bacterial infections</td>
<td>not yet assigned</td>
</tr>
<tr><td> MSH6</td>
<td>MSH6 gene defect part of mismatch repair [MMR] machinery); DNA repair defect<break></break>
600678</td>
<td>AR</td>
<td>Variable IgG, defects; increased IgM in some; normal B cells, low switched memory B cells; Ig-CSR and SHM defects</td>
<td>Family or personal history of cancer</td>
<td>not yet assigned</td>
</tr>
<tr><td colspan="6">4. Isotype or light chain deficiencies with generally normal numbers of B cells</td>
</tr>
<tr><td> Activated PI3K-δ</td>
<td>Mutation in <italic>PIK3CD;</italic>
<italic>p110 encoding for p110 subunit of PI3K</italic>
<break></break>
602839</td>
<td>AD gain of function</td>
<td>Reduced IgG2 and impaired antibody to pneumococci and hemophilus</td>
<td>Respiratory infections, bronchiectasis; autoimmunity; chronic EBV, CMV infection</td>
<td>615513</td>
</tr>
<tr><td> PI3KR1 loss of function</td>
<td>Mutation in <italic>PIK3R1</italic>
 leading to mutations in p85α<break></break>
171833</td>
<td>AD loss of function of p85α (leading to activation of PI3K-δ – as above)</td>
<td>Absent IgA, low IgG</td>
<td>EBV, CMV viremia; growth retardation</td>
<td>616005</td>
</tr>
<tr><td> Ig heavy chain mutations and deletions</td>
<td>Mutation or chromosomal deletion at 14q32</td>
<td>AR</td>
<td>One or more IgG and/or IgA subclasses as well as IgE may be absent</td>
<td>May be asymptomatic</td>
<td></td>
</tr>
<tr><td> IGKC deficiency</td>
<td>Mutations in Kappa constant gene</td>
<td>AR</td>
<td>All immunoglobulins have lambda light chain</td>
<td>Asymptomatic</td>
<td>147200</td>
</tr>
<tr><td> Isolated IgG subclass deficiency</td>
<td>Unknown</td>
<td>Variable</td>
<td>Reduction in one or more IgG subclass</td>
<td>Usually asymptomatic; a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infections</td>
<td></td>
</tr>
<tr><td> IgA with IgG subclass deficiency</td>
<td>Unknown</td>
<td>Variable</td>
<td>Reduced IgA with decrease in one or more IgG subclass</td>
<td>Recurrent bacterial infections</td>
<td></td>
</tr>
<tr><td> Specific antibody deficiency with normal Ig concentrations and normal numbers of B cells</td>
<td>Unknown</td>
<td>Variable</td>
<td>Normal</td>
<td>Reduced ability to produce antibodies to specific antigens</td>
<td></td>
</tr>
<tr><td> Transient hypogammaglobulinemia of infancy with normal numbers of B cells</td>
<td>Unknown</td>
<td>Variable</td>
<td>IgG and IgA decreased</td>
<td>Normal ability to produce antibodies to vaccine antigens, usually not associated with significant infections</td>
<td></td>
</tr>
<tr><td> CARD 11 gain of function</td>
<td>CARD11; scaffold for NF-kB activity in the adaptive immune response; gain of function</td>
<td>AD</td>
<td>Congenital B cell lymphocytosis. High B cell numbers due to constitutive NF-κB activation</td>
<td>Splenomegaly; lymphadenopathy</td>
<td>607210; 606445</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>Total no. of gene in Table <xref rid="Tab3" ref-type="table">3</xref>
: 28</p>
<p>New genes added: <italic>MOGS, TRNT1, TTC37, IN08, MSH6, PI3KR1 AD</italic>
</p>
<p>Notes: Several autosomal recessive disorders that might previously have been called CVID have been added to Table <xref rid="Tab3" ref-type="table">3</xref>
. CD81 is normally co-expressed with CD19 on the surface of B cells. As for CD19 mutations, mutations in CD81 result in normal numbers of peripheral blood B cells, low serum IgG and an increased incidence of glomerulonephritis</p>
<p>Common Variable Immunodeficiency Disorders (CVID) include several clinical and laboratory phenotypes that may be caused by distinct genetic and/or environmental factors. Some patients with CVID and no known genetic defect have markedly reduced numbers of B cells as well as hypogammaglobulinemia. Alterations in <italic>TNFRSF13B (TACI)</italic>
 and <italic>TNFRSF13C (BAFF-R)</italic>
 sequences may represent disease modifying mutations rather than disease causing mutations. A small minority of patients with XLP (Table <xref rid="Tab4" ref-type="table">4</xref>
), WHIM syndrome (Table <xref rid="Tab6" ref-type="table">6</xref>
), ICF (Table <xref rid="Tab2" ref-type="table">2</xref>
), VOD1 (Table <xref rid="Tab2" ref-type="table">2</xref>
), thymoma with immunodeficiency (Good syndrome) or myelodysplasia are first seen by an immunologist because of recurrent infections, hypogammaglobulinemia and normal or reduced numbers of B cells</p>
<p><italic>XL</italic>
 X-linked inheritance, <italic>AR</italic>
 autosomal recessive inheritance, <italic>AD</italic>
 autosomal dominant inheritance<italic>; BTK</italic>
 Bruton tyrosine kinase, <italic>BLNK</italic>
 B cell linker protein</p>
<p><italic>AID</italic>
 activation-induced cytidine deaminase, <italic>UNG</italic>
 uracil-DNA glycosylase, <italic>Ig(κ)</italic>
 immunoglobulin or κ light-chain type</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="Tab4"><label>Table 4</label>
<caption><p>Diseases of immune dysregulation</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th>Disease</th>
<th>Genetic defect/Presumed pathogenesis<break></break>
Gene OMIM</th>
<th>Inheritance</th>
<th>Circulating T Cells</th>
<th>Circulating B cells</th>
<th>Functional defect</th>
<th>Associated Features</th>
<th>Phenotype OMIM<break></break>
number</th>
</tr>
</thead>
<tbody><tr><td colspan="8">1. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes</td>
</tr>
<tr><td colspan="8"> 1.1. FHL syndromes without hypopigmentation</td>
</tr>
<tr><td>  Perforin deficiency (FHL2)</td>
<td>Mutations in <italic>PRF1</italic>
; perforin is a major cytolytic protein<break></break>
170280</td>
<td>AR</td>
<td>Increased activated T cells</td>
<td>Normal</td>
<td>Decreased to absent NK and CTL activities cytotoxicity</td>
<td>Fever, Hepato-Splenomegaly (HSMG), Hemophagocytic lymphohistiocytosis (HLH), Cytopenias</td>
<td>603553</td>
</tr>
<tr><td>  (UNC13D / Munc13-4 deficiency (FHL3)</td>
<td>Mutations in <italic>UNC13D</italic>
; required to prime vesicles for fusion<break></break>
608897</td>
<td>AR</td>
<td>Increased activated T cells</td>
<td>Normal</td>
<td>Decreased to absent NK and CTL activities<break></break>
(cytotoxicity and/or<break></break>
degranulation)</td>
<td>Fever, HSMG, HLH, Cytopenias,</td>
<td>608898</td>
</tr>
<tr><td>  Syntaxin 11 deficiency, (FHL4)</td>
<td>Mutations in <italic>STX11</italic>
, required for secretory vesicle fusion with the cell membrane<break></break>
605014</td>
<td>AR</td>
<td>Increased activated T cells</td>
<td>Normal</td>
<td>Decreased NK activity (cytotoxicity and/or degranulation)</td>
<td>Fever, HSMG, HLH, Cytopenias,</td>
<td>603552</td>
</tr>
<tr><td>  STXBP2 / Munc18-2 deficiency (FHL5)</td>
<td>Mutations in <italic>STXBP2</italic>
, required for secretory vesicle fusion with the cell membrane<break></break>
601717</td>
<td>AR or AD</td>
<td>Increased activated T cells</td>
<td>Normal</td>
<td>Decreased NK and CTL activities (cytotoxicity and/or degranulation)</td>
<td>Fever, HSMG, HLH, Cytopenias,</td>
<td>613101</td>
</tr>
<tr><td>  SH2D1A deficiency (XLP1)</td>
<td>Mutations in <italic>SH2D1A</italic>
 encoding an adaptor protein regulating intracellular signaling<break></break>
300490</td>
<td>XL</td>
<td>Normal or increased activated T cells</td>
<td>Reduced Memory B cells</td>
<td>partially defective NK cell and CTL cytotoxic activity</td>
<td>Clinical and immunologic features triggered by EBV infection: HLH, lymphoproliferation, Aplastic anaemia, lymphoma.<break></break>
Hypogammaglobulinemia, absent iNKT cells</td>
<td>308240</td>
</tr>
<tr><td>  XIAP deficiency (XLP2)</td>
<td>Mutations in <italic>XIAP/ BIRC4</italic>
 encoding an inhibitor of apoptosis<break></break>
300079</td>
<td>XL</td>
<td>Normal or Increased activated T cells; low/normal iNK T cells</td>
<td>Normal or reduced Memory B cells</td>
<td>Increased T cells susceptibility to apoptosis to CD95 and enhanced activation-induced cell death (AICD)</td>
<td>EBV infection, Splenomegaly, lymphoproliferation HLH, Colitis, IBD, hepatitis<break></break>
Low iNKT cells</td>
<td>300635</td>
</tr>
<tr><td colspan="8"> 1.2. FHL syndromes with hypopigmentation</td>
</tr>
<tr><td>  Chediak-Higashi syndrome</td>
<td>Mutations in <italic>LYST</italic>
, impaired lysosomal trafficking<break></break>
606897</td>
<td>AR</td>
<td>Increased activated T cells</td>
<td>Normal</td>
<td>Decreased NK and CTL activities (cytotoxicity and/or degranulation)</td>
<td>Partial albinism, recurrent infections, fever, HSMG, HLH<break></break>
Giant lysosomes, neutropenia, cytopenias, bleeding tendency, progressive neurological dysfunction</td>
<td>214500</td>
</tr>
<tr><td>  Griscelli syndrome, type2</td>
<td>Mutations in <italic>RAB27A</italic>
 encoding a GTPase that promotes docking of secretory vesicles to the cell membrane<break></break>
603868</td>
<td>AR</td>
<td>Normal</td>
<td>Normal</td>
<td>Decreased NK and CTL activities (cytotoxicity and/or degranulation)</td>
<td>Partial albinism, fever, HSMG, HLH, cytopenias</td>
<td>607624</td>
</tr>
<tr><td>  Hermansky-Pudlak syndrome, type 2</td>
<td>Mutations in <italic>AP3B1</italic>
 gene, encoding for the β subunit of the AP-3 complex<break></break>
603401</td>
<td>AR</td>
<td>Normal</td>
<td>Normal</td>
<td>Decreased NK and CTL activities (cytotoxicity and/or degranulation)</td>
<td>Partial albinism, recurrent infections, pulmonary fibrosis<break></break>
Increased bleeding, neutropenia, HLH</td>
<td>608233</td>
</tr>
<tr><td>  Hermansky-Pudlak syndrome, type 9</td>
<td>Mutations in <italic>PLDN</italic>
, encoding Pallidin, a component of the biogenesis of lysosome-related organelles complex-1 (BLOC-1)<break></break>
604310</td>
<td>AR</td>
<td>(Not assessed; leukopenia)</td>
<td>(Not assessed, leukopenia)</td>
<td>Decreased NK cell cytolytic activity</td>
<td>Oculocutaneous albinism, recurrent cutaneous infections, leukopenia, thrombocytopenia</td>
<td>614171</td>
</tr>
<tr><td colspan="8">2. T regulatory cells genetic defects</td>
</tr>
<tr><td> IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked</td>
<td>Mutations in <italic>FOXP3</italic>
, encoding a T cell transcription factor<break></break>
300292</td>
<td>XL</td>
<td>Normal</td>
<td>Normal</td>
<td>Lack of (and/or impaired function of) CD4<sup>+</sup>
 CD25<sup>+</sup>
 FOXP3<sup>+</sup>
 regulatory T cells (Tregs)</td>
<td>Autoimmune enteropathy, early onset diabetes, thyroiditis hemolytic anemia, thrombocytopenia, eczema<break></break>
Elevated IgE, IgA</td>
<td>304790</td>
</tr>
<tr><td> CD25 deficiency</td>
<td>Mutations in <italic>IL2RA</italic>
, encoding IL-2Rα chain, 147730</td>
<td>AR</td>
<td>Normal to decreased</td>
<td>Normal</td>
<td>No CD4 + C25+ cells with impaired function of Tregs cells</td>
<td>Lymphoproliferation, autoimmunity. Impaired T cell proliferation</td>
<td>606367</td>
</tr>
<tr><td> CTLA4 deficiency (ALPSV)</td>
<td>Mutations in <italic>CTLA4</italic>
, encoding Cytotoxic T Lymphocyte antigen 4, a protein that negatively regulate T cell receptor signaling and T cell activation.<break></break>
123890</td>
<td>AD</td>
<td>Decreased</td>
<td>Decreased</td>
<td>Impaired function of Treg cells.</td>
<td>Autoimmune cytopenias, enteropathy, interstitial lung disease, extra-lymphoid lymphocytic infiltration recurrent infections,</td>
<td>616100</td>
</tr>
<tr><td> STAT3 GOF mutations</td>
<td>Mutations in <italic>STAT3</italic>
, encoding Signal Transducer and activator 3<break></break>
102582</td>
<td>AD</td>
<td>Decreased</td>
<td>Decreased</td>
<td>Enhanced STAT3 signaling, leading to increased Th17 cell differentiation, lymphoproliferation and autoimmunity. Decreased Treg cell numbers and impaired phenotype</td>
<td>Lymphoproliferation, Solid organ autoimmunity, recurrent infections.</td>
<td>615952</td>
</tr>
<tr><td colspan="8">3. Autoimmunity with or without lymphoproliferation</td>
</tr>
<tr><td> APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy</td>
<td>Mutations in <italic>AIRE</italic>
, encoding a transcription regulator needed to establish thymic self-tolerance<break></break>
607358</td>
<td>AR</td>
<td>Normal</td>
<td>Normal</td>
<td>AIRE-1 serves as check-point in the thymus for negative selection of autoreactive T cells and for generation of Tregs</td>
<td>Autoimmunity: hypoparathyroidism hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction and other endocrine abnormalities, chronic mucocutaneous candidiasis, dental enamel hypoplasia, alopecia areata<break></break>
Enteropathy, Pernicious anemia,</td>
<td>240300</td>
</tr>
<tr><td> ITCH deficiency</td>
<td>Mutations in <italic>ITCH</italic>
, an E3 ubiquitin ligase catalyzes the transfer of ubiquitin to a signaling proteins in the cell including phospholipase Cγ1 (PLCγ1)<break></break>
606409</td>
<td>AR</td>
<td>Not assessed</td>
<td>Not assessed</td>
<td>Itch deficiency may cause immune dysregulation by affecting both anergy induction in auto-reactive effector T cells and generation of Tregs</td>
<td>Early-onset chronic lung disease (interstitial pneumonitis)<break></break>
Autoimmune disorder (thyroiditis, type I diabetes, chronic diarrhea/enteropathy, and hepatitis)<break></break>
Failure to thrive, developmental delay, dysmorphic facial features</td>
<td>613385</td>
</tr>
<tr><td> Tripeptidyl-Peptidase II Deficiency</td>
<td>Mutations in <italic>TPP2</italic>
, encoding tripeptidyl-peptidase II, serine exopeptidase involved in extralysosomal peptide degradation<break></break>
190470</td>
<td>AR</td>
<td>Decreased</td>
<td>Decreased</td>
<td>TPP2 deficiency results in premature immunosenescence and immune dysregulation</td>
<td>Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections,</td>
<td>Not yet assigned</td>
</tr>
<tr><td colspan="8">3. Autoimmune lymphoproliferative syndrome (ALPS)</td>
</tr>
<tr><td> ALPS-FAS</td>
<td>Germinal mutations in <italic>TNFRSF6</italic>
, encoding CD95/Fas cell surface apoptosis receptor**<break></break>
134637</td>
<td>AD<break></break>
AR***</td>
<td>Increased CD4<sup>−</sup>
CD8<sup>−</sup>
TCRαβ double negative (DN) T cells</td>
<td>Normal, low memory B cells</td>
<td>Apoptosis defect FAS mediated</td>
<td>Splenomegaly, adenopathies, Autoimmune cytopenias, increased lymphoma risk.<break></break>
IgG and A normal or increased<break></break>
Elevated FasL and IL-10, vitamin B12</td>
<td>601859</td>
</tr>
<tr><td> ALPS-FASLG</td>
<td>Mutations in <italic>TNFSF6</italic>
, Fas ligand for CD95 apoptosis<break></break>
134638</td>
<td>AR</td>
<td>Increased DN T cells</td>
<td>Normal</td>
<td>Apoptosis defect FAS mediated</td>
<td>Splenomegaly, adenopathies, autoimmune cytopenias, SLE;<break></break>
Soluble FasL is not elevated</td>
<td>601859</td>
</tr>
<tr><td> ALPS-Caspase10</td>
<td>Mutations in <italic>CASP10</italic>
, intracellular apoptosis pathway<break></break>
601762</td>
<td>AD</td>
<td>Increased DN T cells</td>
<td>Normal</td>
<td>Defective lymphocyte apoptosis</td>
<td>Adenopathies, splenomegaly, autoimmunity.</td>
<td>603909</td>
</tr>
<tr><td> ALPS-Caspase 8</td>
<td>Mutations in <italic>CASP8</italic>
, intracellular apoptosis and activation pathways<break></break>
601763</td>
<td>AR</td>
<td>Slightly increased DN T cells</td>
<td>Normal</td>
<td>Defective lymphocyte apoptosis and activation</td>
<td>Adenopathies, splenomegaly, Bacterial and viral infections,<break></break>
Hypogammaglobulinemia</td>
<td>607271</td>
</tr>
<tr><td> FADD deficiency</td>
<td>Mutations in <italic>FADD</italic>
 encoding an adaptor molecule interacting with FAS, and promoting apoptosis<break></break>
602457</td>
<td>AR</td>
<td>Increased DN T cells</td>
<td>Normal</td>
<td>Defective lymphocyte apoptosis</td>
<td>Functional hyposplenism,<break></break>
Bacterial and viral infections,<break></break>
Recurrent episodes of encephalopathy and liver dysfunction.</td>
<td>613759</td>
</tr>
<tr><td> PRKC delta deficiency</td>
<td>Mutations in <italic>PRKCD</italic>
,<break></break>
encoding a member of the protein kinase C family critical for regulation of cell survival, proliferation and apoptosis<break></break>
176977</td>
<td>AR</td>
<td>Normal</td>
<td>Low memory B cells and<break></break>
Elevation of CD5 B cells</td>
<td>Apoptotic defect in B cells</td>
<td>Recurrent infections; EBV chronic infection<break></break>
Lymphoproliferation<break></break>
SLE-like autoimmunity (Nephrotic and antiphospholipid syndromes)<break></break>
HypoIgG</td>
<td>615559</td>
</tr>
<tr><td colspan="8">4. Immune dysregulation with colitis</td>
</tr>
<tr><td> IL-10 deficiency</td>
<td>Mutations in <italic>IL10</italic>
,<break></break>
encoding IL-10<break></break>
124092</td>
<td>AR</td>
<td>Normal</td>
<td>Normal</td>
<td>No functional IL-10 secretion</td>
<td>Inflammatory bowel disease (IBD) Folliculitis,<break></break>
Recurrent respiratory diseases,<break></break>
Arthritis,</td>
<td>not assigned</td>
</tr>
<tr><td> IL-10Rα deficiency</td>
<td>Mutations in <italic>IL10RA</italic>
,<break></break>
encoding IL-10R1<break></break>
146933</td>
<td>AR</td>
<td>Normal</td>
<td>Normal</td>
<td>Leukocytes no response<break></break>
to IL-10</td>
<td>IBD, Folliculitis,<break></break>
Recurrent respiratory diseases,<break></break>
Arthritis, Lymphoma</td>
<td>613148</td>
</tr>
<tr><td> IL-10Rβ deficiency</td>
<td>Mutations in <italic>IL10RB</italic>
,<break></break>
encoding IL-10R2<break></break>
123889</td>
<td>AR</td>
<td>Normal</td>
<td>Normal</td>
<td>Leukocytes no response<break></break>
to IL-10, IL-22, IL-26, IL-28A, IL-28B, and IL-29</td>
<td>IBD, Folliculitis,<break></break>
Recurrent respiratory diseases,<break></break>
Arthritis, Lymphoma</td>
<td>612567</td>
</tr>
<tr><td> NFAT5 haploinsufficiency</td>
<td>Hemizygous deletion of <italic>NFAT5</italic>
<break></break>
604708</td>
<td>AD</td>
<td>Normal</td>
<td>Normal</td>
<td>Decreased memory B cells and plasmablasts</td>
<td>IBD, recurrent sinopulmonary infections</td>
<td>Not yet assigned</td>
</tr>
<tr><td colspan="8">5. Type 1 Interferonopathies</td>
</tr>
<tr><td> TREX1 deficiency, Aicardi-Goutieres syndrome 1 (AGS1)</td>
<td>Mutations in <italic>TREX1</italic>
, encoding nuclease involves in clearing cellular nucleic debris<break></break>
606609</td>
<td>AR<break></break>
AD*****</td>
<td>Not assessed</td>
<td>Not assessed</td>
<td>Intracellular accumulation of abnormal single-stranded (ss) DNA species leading to increased CSF alpha-IFN production</td>
<td>Progressive encephalopathy Intracranial calcifications,<break></break>
Cerebral atrophy, leukodystrophy,<break></break>
HSMG, Thrombocytopenia,<break></break>
Elevated hepatic transaminases<break></break>
Chronic cerebrospinal fluid (CSF) lymphocytosis</td>
<td>225750</td>
</tr>
<tr><td> RNASEH2B deficiency, AGS2</td>
<td>Mutations in <italic>RNASEH2B</italic>
, encoding nuclease subunit involves in clearing cellular nucleic debris<break></break>
610326</td>
<td>AR</td>
<td>Not assessed</td>
<td>Not assessed</td>
<td>Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production</td>
<td>Progressive encephalopathy Intracranial calcifications,<break></break>
Cerebral atrophy, leukodystrophy,<break></break>
HSMG, thrombocytopenia,<break></break>
Elevated hepatic transaminases<break></break>
Chronic CSF lymphocytosis</td>
<td>610181</td>
</tr>
<tr><td> RNASEH2C deficiency, AGS3</td>
<td>Mutations in <italic>RNASEH2C</italic>
, encoding nuclease subunit involves in clearing cellular nucleic debris<break></break>
610330</td>
<td>AR</td>
<td>Not assessed</td>
<td>Not assessed</td>
<td>Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production</td>
<td>Progressive encephalopathy Intracranial calcifications,<break></break>
Cerebral atrophy, leukodystrophy,<break></break>
HSMG, thrombocytopenia,<break></break>
Elevated hepatic transaminases<break></break>
Chronic CSF lymphocytosis</td>
<td>610329</td>
</tr>
<tr><td> RNASEH2A deficienc y, AGS4</td>
<td>Mutations in <italic>RNASEH2A</italic>
, encoding nuclease subunit involves in clearing cellular nucleic debris<break></break>
606034</td>
<td>AR</td>
<td>Not assessed</td>
<td>Not assessed</td>
<td>Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production</td>
<td>Progressive encephalopathy Intracranial calcifications,<break></break>
Cerebral atrophy, leukodystrophy,<break></break>
HSMG, thrombocytopenia,<break></break>
Elevated hepatic transaminases<break></break>
Chronic CSF lymphocytosis</td>
<td>610333</td>
</tr>
<tr><td> SAMHD1 deficiency, AGS5</td>
<td>Mutations in <italic>SAMHD1</italic>
, encoding negative regulator of the immunostimulatory DNA response<break></break>
606754</td>
<td>AR</td>
<td>Not assessed</td>
<td>Not assessed</td>
<td>Induction of the cell intrinsic antiviral response, apoptosis, and mitochondrial DNA destruction leading to increased CSF alpha-IFN production</td>
<td>Progressive encephalopathy Intracranial calcifications,<break></break>
Cerebral atrophy, leukodystrophy,<break></break>
HSMG, thrombocytopenia, anemia elevated lactates<break></break>
Chronic CSF lymphocytosis,<break></break>
Skin vascularitis, mouth ulcers, arthropathy</td>
<td>612952</td>
</tr>
<tr><td> ADAR1 deficiency, AGS6</td>
<td>Mutations in <italic>ADAR1</italic>
, encoding a RNA-specific adenosine deaminase<break></break>
146920</td>
<td>AR</td>
<td>Not assessed</td>
<td>Not assessed</td>
<td>Catalyzes the deamination of adenosine to inosine in dsRNA substrates Markedly elevated CSF IFN-alpha</td>
<td>Progressive encephalopathy intracranial calcification,<break></break>
Severe developmental delay, leukodystrophy</td>
<td>615010</td>
</tr>
<tr><td> Aicardi-Goutieres syndrome 7 (AGS7)</td>
<td><italic>IFIH1</italic>
<break></break>
606951</td>
<td>AD</td>
<td>Not assessed</td>
<td>Not assessed</td>
<td>IFIH1 gene encodes a cytoplasmic viral RNA receptor that activates type I interferon signaling through the MAVS adaptor molecule</td>
<td>Progressive encephalopathy intracranial calcification,<break></break>
Severe developmental delay, leukodystrophy</td>
<td>615846</td>
</tr>
<tr><td> Spondyloenchondro-dysplasia with immune dysregulation (SPENCD)</td>
<td>Mutations in <italic>ACP5</italic>
, encoding tartrate-resitant acid phosphatase (TRAP)<break></break>
171640</td>
<td>AR</td>
<td>Not assessed</td>
<td>Not assessed</td>
<td>Upregulation of IFN-alpha and type I IFN-stimulated genes</td>
<td>Recurrent bacterial and viral infections,<break></break>
Intracranial calcification,<break></break>
SLE-like autoimmunity (Sjögren’s syndrome, hypothyroidism, inflammatory myositis, Raynaud’s disease and vitiligo), hemolytic anemia, thrombocytopenia,<break></break>
skeletal dysplasia, short stature</td>
<td>607944</td>
</tr>
<tr><td> STING--associated vasculopathy, infantile-onset</td>
<td><italic>TMEM173 encoding for</italic>
 STIMULATOR OF INTERFERON GENES<break></break>
612374</td>
<td>AR</td>
<td>Not assessed</td>
<td>Not assessed</td>
<td>STING activates both the NF-kappa-B and IRF3 transcription pathways to induce expression of IFN-alpha and IFN-beta and exert a potent antiviral effect</td>
<td>Severe infantile-onset autoinfammatory vasculopathy,</td>
<td>615934</td>
</tr>
<tr><td> ADA2 deficiency</td>
<td>Mutations in CECR1; encoding ADA2<break></break>
607575</td>
<td>AR</td>
<td>Not assessed</td>
<td>Not assessed</td>
<td>ADAs deactivate extracellular adenosine and terminate signaling through adenosine receptors</td>
<td>Polyarteritis nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever</td>
<td>615688</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>Total no. of genes in Table <xref rid="Tab4" ref-type="table">4</xref>
: 37</p>
<p>New genes added: <italic>PLDN, CTLA4, TPP2, NFAT5, IFIH1, TMEM173, CECR1, STAT 3 (GOF)</italic>
</p>
<p><italic>XL</italic>
 X-linked inheritance, <italic>AR</italic>
 autosomal recessive inheritance, <italic>AD</italic>
 autosomal dominant inheritance, <italic>FHL</italic>
 familial hemophagocytic lymphohistiocytosis, <italic>HLH</italic>
 Hemophagocytic lymphohistiocytosis, <italic>HSMG</italic>
 hepato-splenomegaly, <italic>DN</italic>
 double-negative, <italic>SLE</italic>
 systemic lupus erythematous, <italic>IBD</italic>
 inflammatory bowel disease, <italic>CSF</italic>
 chronic cerebrospinal fluid</p>
<p>** Somatic mutations of <italic>TNFRSF6</italic>
 cause a similar phenotype (ALPS-sFAS) see Table <xref rid="Tab9" ref-type="table">9</xref>
. Germinal mutation and somatic mutations of <italic>TNFRSF6</italic>
 can be associated in some ALPS-FAS patients</p>
<p>*** AR ALPS-FAS patients have a most severe clinical phenotype</p>
<p>**** Somatic mutations in KRAS or NRAS can give this clinical phenotype associated auto-immune leukoproliferative disease (RALD) and are now include in Table <xref rid="Tab9" ref-type="table">9</xref>
 entitled Phenocopies of PID</p>
<p>***** <italic>de novo</italic>
 dominant TREX1 mutations have been reported</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="Tab5"><label>Table 5</label>
<caption><p>Congenital defects of phagocyte number, function, or both</p>
</caption>
<table frame="hsides" rules="groups"><tbody><tr><td>Disease</td>
<td>Genetic defect/<break></break>
Presumed pathogenesis<break></break>
OMIM gene</td>
<td>Inheritance</td>
<td>Affected cells</td>
<td>Affected function</td>
<td>Associated features</td>
<td>Phenotype<break></break>
OMIM number</td>
</tr>
<tr><td colspan="7">1) Congenital neutropenias</td>
</tr>
<tr><td> Elastase deficiency (SCN1)</td>
<td>Mutation in <italic>ELANE:</italic>
 misfolded protein response, increased apoptosis<break></break>
130130</td>
<td>AD</td>
<td>N</td>
<td>Myeloid differentiation</td>
<td>Susceptibility to MDS/leukemia</td>
<td>202700</td>
</tr>
<tr><td> GFI 1 deficiency (SCN2)</td>
<td>Mutation in <italic>GFI1</italic>
: loss of repression of ELANE<break></break>
600871</td>
<td>AD</td>
<td>N</td>
<td>Myeloid differentiation</td>
<td>B/T lymphopenia</td>
<td>613107</td>
</tr>
<tr><td> Kostmann Disease (SCN3)</td>
<td>Mutation in <italic>HAX1</italic>
: control of apoptosis<break></break>
605998</td>
<td>AR</td>
<td>N</td>
<td>Myeloid differentiation</td>
<td>Cognitive and neurological defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia</td>
<td>610738</td>
</tr>
<tr><td> G6PC3 deficiency (SCN4)</td>
<td>Mutation in <italic>G6PC3</italic>
: abolished enzymatic activity of glucose-6-phosphatase, aberrant glycosylation, and enhanced apoptosis of N and F<break></break>
611045</td>
<td>AR</td>
<td>N + F</td>
<td>Myeloid differentiation, chemotaxis,<break></break>
O<sub>2</sub>
<sup>−</sup>
 production</td>
<td>Structural heart defects, urogenital abnormalities,<break></break>
inner ear deafness, and venous angiectasias of trunks and limbs</td>
<td>612541</td>
</tr>
<tr><td> VPS45 deficiency (SCN5)</td>
<td>Mutation in <italic>VPS45 controls vesicular trafficking</italic>
<break></break>
610035</td>
<td>AR</td>
<td>N+F</td>
<td>Myeloid differentiation, migration</td>
<td>Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly,</td>
<td>615285</td>
</tr>
<tr><td> Glycogen storage disease<break></break>
 type 1b</td>
<td>Mutation in <italic>G6PT1</italic>
: Glucose-6-phosphate transporter 1<break></break>
602671</td>
<td>AR</td>
<td>N + M</td>
<td>Myeloid differentiation, chemotaxis,<break></break>
O<sub>2</sub>
<sup>−</sup>
 production</td>
<td>Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly</td>
<td>232220</td>
</tr>
<tr><td> Cyclic neutropenia</td>
<td>Mutation in <italic>ELANE</italic>
: misfolded protein response<break></break>
130130</td>
<td>AD</td>
<td>N</td>
<td>Differentiation</td>
<td>Oscillations of other leukocytes and platelets</td>
<td>162800</td>
</tr>
<tr><td> X-linked neutropenia/ myelodysplasia</td>
<td>Mutation in <italic>WAS:</italic>
 Regulator of actin cytoskeleton (loss of autoinhibition)<break></break>
300392</td>
<td>XL, gain of function</td>
<td>N + M</td>
<td>Mitosis</td>
<td>Monocytopenia</td>
<td>300299</td>
</tr>
<tr><td> P14/LAMTOR2 deficiency</td>
<td>Mutation in <italic>ROBLD3/LAMTOR2</italic>
: Endosomal adaptor protein 14<break></break>
610389</td>
<td>AR</td>
<td>N+L<break></break>
Mel</td>
<td>Endosome biogenesis</td>
<td>Neutropenia<break></break>
Hypogammaglobulinemia<break></break>
↓CD8 cytotoxicity<break></break>
Partial albinism<break></break>
Growth failure</td>
<td>610798</td>
</tr>
<tr><td> Barth Syndrome</td>
<td>Mutation in Tafazzin (<italic>TAZ</italic>
) gene: Abnormal lipid structure of mitochondrial membrane, defective carnitine metabolism<break></break>
300394</td>
<td>XL</td>
<td>N</td>
<td>Myeloid differentiation</td>
<td>Cardiomyopathy, myopathy, growth retardation</td>
<td>302060</td>
</tr>
<tr><td> Cohen syndrome</td>
<td>Mutation in <italic>COH1</italic>
 gene: Pg unknown 607817</td>
<td>AR</td>
<td>N</td>
<td>Myeloid differentiation</td>
<td>Retinopathy, developmental delay, facial dysmorphisms</td>
<td>216550</td>
</tr>
<tr><td> Clericuzio syndrome<break></break>
 Poikiloderma with neutropenia</td>
<td>Mutation in <italic>C16ORF57 (USB1)</italic>
, affects genomic integrity<break></break>
613276</td>
<td>AR</td>
<td>N</td>
<td>Myeloid differentiation</td>
<td>Poikiloderma, MDS</td>
<td>604173</td>
</tr>
<tr><td> JAGN1 deficiency</td>
<td>Mutations in JAGN1, regulates secretory pathway<break></break>
616012</td>
<td>AR</td>
<td>N</td>
<td>Myeloid differentiation</td>
<td>Some with a bone phenotype</td>
<td>616022</td>
</tr>
<tr><td> 3-Methylglutaconic aciduria</td>
<td>Mutations in CLPB<break></break>
616254</td>
<td>AR</td>
<td>N</td>
<td>Myeloid differentiation</td>
<td>Microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR</td>
<td>Not yet assigned</td>
</tr>
<tr><td> G-CSF receptor deficiency</td>
<td>Mutations in CSF3R, the growth factor receptor<break></break>
138971</td>
<td>AR</td>
<td>N</td>
<td>Myeloid differentiation</td>
<td>Poor response to GCSF</td>
<td>162830</td>
</tr>
<tr><td> Disease</td>
<td>Genetic defect/<break></break>
Presumed pathogenesis</td>
<td>Inheritance</td>
<td>Affected cells</td>
<td>Affected function</td>
<td>Associated features</td>
<td>OMIM number</td>
</tr>
<tr><td colspan="7">2. Defects of Motility</td>
</tr>
<tr><td> Leukocyte adhesion deficiency<break></break>
type 1 (LAD1)</td>
<td>Mutation in <italic>ITGB2</italic>
: B chain for adhesion proteins CD18/CD11<break></break>
600065</td>
<td>AR</td>
<td>N + M +<break></break>
L + NK</td>
<td>Adherence,<break></break>
Chemotaxis,<break></break>
Endocytosis,<break></break>
T/NK cytotoxicity</td>
<td>Delayed cord separation, skin ulcers<break></break>
Periodontitis<break></break>
Leukocytosis</td>
<td>116920</td>
</tr>
<tr><td> Leukocyte adhesion deficiency type 2 (LAD2)</td>
<td>Mutation in <italic>SLC35C1</italic>
: GDP-Fucose transporter<break></break>
605881</td>
<td>AR</td>
<td>N + M</td>
<td>Rolling,<break></break>
chemotaxis</td>
<td>Mild LAD type 1 features<break></break>
plus hh-blood group plus mental and growth retardation</td>
<td>266265</td>
</tr>
<tr><td> Leukocyte adhesion deficiency type 3 (LAD3)</td>
<td>Mutation in <italic>KINDLIN3</italic>
:<break></break>
Rap1-activation of β1-3 integrins<break></break>
607901</td>
<td>AR</td>
<td>N + M +<break></break>
L + NK</td>
<td>Adherence, chemotaxis</td>
<td>LAD type 1 plus bleeding tendency</td>
<td>612840</td>
</tr>
<tr><td> Rac 2 deficiency</td>
<td>Mutation in <italic>RAC2</italic>
: Regulation of actin cytoskeleton<break></break>
602049</td>
<td>AD</td>
<td>N</td>
<td>Adherence,<break></break>
chemotaxis<break></break>
O<sub>2</sub>
<sup>−</sup>
 production</td>
<td>Poor wound healing, leukocytosis</td>
<td>608203</td>
</tr>
<tr><td> β-actin deficiency</td>
<td>Mutation in <italic>ACTB</italic>
: Cytoplasmic Actin<break></break>
102630</td>
<td>AD</td>
<td>N + M</td>
<td>Motility</td>
<td>Mental retardation, short stature</td>
<td>243310</td>
</tr>
<tr><td> Localized juvenile periodontitis</td>
<td>Mutation in <italic>FPR1</italic>
: Formylated peptide receptor<break></break>
136537</td>
<td>AR</td>
<td>N</td>
<td>Formylpeptide induced chemotaxis</td>
<td>Periodontitis only</td>
<td>Not assigned</td>
</tr>
<tr><td> Papillon-Lefèvre Syndrome</td>
<td>Mutation in <italic>CTSC</italic>
: Cathepsin C activation of serine proteases<break></break>
602365</td>
<td>AR</td>
<td>N + M</td>
<td>Chemotaxis</td>
<td>Periodontitis, palmoplantar hyperkeratosis in some patients</td>
<td>245000</td>
</tr>
<tr><td> Specific granule deficiency</td>
<td>Mutation in <italic>C/EBPE</italic>
: myeloid transcription factor<break></break>
189965</td>
<td>AR</td>
<td>N</td>
<td>Chemotaxis</td>
<td>Neutrophils with bilobed nuclei</td>
<td>245480</td>
</tr>
<tr><td> Shwachman-Diamond Syndrome</td>
<td>Mutation in <italic>SBDS:</italic>
 Defective ribosome synthesis607444</td>
<td>AR</td>
<td>N</td>
<td>Chemotaxis</td>
<td>Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia</td>
<td>260400</td>
</tr>
<tr><td colspan="7">3. Defects of Respiratory Burst</td>
</tr>
<tr><td> X-linked chronic granulomatous disease (CGD)</td>
<td>Mutation in <italic>CYBB</italic>
: Electron transport protein (gp91phox)<break></break>
300481</td>
<td>XL</td>
<td>N + M</td>
<td>Killing (faulty O<sub>2</sub>
<sup>−</sup>
 production)</td>
<td>McLeod phenotype in patients with deletions extending into the contiguous Kell locus</td>
<td>306400</td>
</tr>
<tr><td> Autosomal recessive CGD</td>
<td>Mutation in <italic>CYBA</italic>
: Electron transport protein (p22phox)<break></break>
608508</td>
<td>AR</td>
<td>N + M</td>
<td>Killing (faulty O<sub>2</sub>
<sup>−</sup>
 production)</td>
<td>Infections, autoinflammatory phenotype</td>
<td>233690</td>
</tr>
<tr><td> Autosomal recessive CGD</td>
<td>Mutation in <italic>NCF1</italic>
: Adapter protein (p47phox)<break></break>
608512</td>
<td>AR</td>
<td>N + M</td>
<td>Killing (faulty O<sub>2</sub>
<sup>−</sup>
 production)</td>
<td>Infections, autoinflammatory phenotype</td>
<td>233700</td>
</tr>
<tr><td> Autosomal recessive CGD</td>
<td>Mutation in <italic>NCF2</italic>
: Activating protein (p67phox)<break></break>
608515</td>
<td>AR</td>
<td>N + M</td>
<td>Killing (faulty O<sub>2</sub>
<sup>−</sup>
 production)</td>
<td>Infections, autoinflammatory phenotype</td>
<td>233710</td>
</tr>
<tr><td> Autosomal recessive CGD</td>
<td>Mutation in <italic>NCF4</italic>
: Activating protein (p40 phox)<break></break>
601488</td>
<td>AR</td>
<td>N + M</td>
<td>Killing (faulty O<sub>2</sub>
<sup>−</sup>
 production)</td>
<td>Infections, autoinflammatory phenotype</td>
<td>613960</td>
</tr>
<tr><td colspan="7">4. Other Defects</td>
</tr>
<tr><td> GATA2 deficiency (Mono MAC syndrome)</td>
<td>Mutations in <italic>GATA2</italic>
: loss of stem cells<break></break>
137295</td>
<td>AD</td>
<td>Monocytes + peripheral DC; low NK cells</td>
<td>Multi lineage cytopenias</td>
<td>Susceptibility to <italic>Mycobacteria</italic>
, papilloma viruses, histoplasmosis, alveolar proteinosis, MDS/AML/CMML</td>
<td>614286<break></break>
614172</td>
</tr>
<tr><td> Pulmonary alveolar proteinosis*</td>
<td>Mutation in <italic>CSF2RA</italic>
<break></break>
306250</td>
<td>Biallelic mutations in pseudoautosomal gene</td>
<td>Alveolar macrophages</td>
<td>GM-CSF signaling</td>
<td>Alveolar proteinosis</td>
<td>300770</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>Total no. of genes in Table <xref rid="Tab5" ref-type="table">5</xref>
: 31</p>
<p>New genes added: <italic>JAGN1, CLBP, CSF3R</italic>
</p>
</table-wrap-foot>
</table-wrap>
</p>
<p><table-wrap id="Tab6"><label>Table 6</label>
<caption><p>Defects in Intrinsic and Innate Immunity</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th>Disease</th>
<th>Genetic defect/Presumed pathogenesis<break></break>
OMIM gene</th>
<th>Inheritance</th>
<th>Affected Cell</th>
<th>Functional Defect</th>
<th>Associated Features</th>
<th>Phenotype<break></break>
OMIM Number</th>
</tr>
</thead>
<tbody><tr><td colspan="7">1. Medelian Susceptibility to mycobacterial disease (MSMD)</td>
</tr>
<tr><td> IL-12 and IL-23 receptor β1 chain deficiency</td>
<td>Mutation in <italic>IL12RB1</italic>
: IL-12 and IL-23 receptor β1 chain<break></break>
601604</td>
<td>AR</td>
<td>L + NK</td>
<td>IFN-γ secretion</td>
<td>Susceptibility to <italic>Mycobacteria</italic>
 and <italic>Salmonella</italic>
</td>
<td>614891</td>
</tr>
<tr><td> IL-12p40 deficiency</td>
<td>Mutation in <italic>IL12B :</italic>
 subunit p40 of IL12/IL23<break></break>
161561</td>
<td>AR</td>
<td>M</td>
<td>IFN-γ secretion</td>
<td>Susceptibility to <italic>Mycobacteria</italic>
 and <italic>Salmonella</italic>
</td>
<td>614890</td>
</tr>
<tr><td> IFN-γ receptor 1 deficiency</td>
<td>Mutation in <italic>IFNGR1</italic>
:<break></break>
IFN-γR ligand binding chain<break></break>
107470</td>
<td>AR</td>
<td>M + L</td>
<td>IFN-γ binding and signaling</td>
<td>Susceptibility to <italic>Mycobacteria</italic>
 and <italic>Salmonella</italic>
</td>
<td>209950</td>
</tr>
<tr><td> IFN-γ receptor 1 deficiency</td>
<td>Mutation in <italic>IFNGR1</italic>
:<break></break>
IFN-γR ligand binding chain<break></break>
107470</td>
<td>AD</td>
<td>M + L</td>
<td>IFN-γ binding and signaling</td>
<td>Susceptibility to <italic>Mycobacteria</italic>
 and <italic>Salmonella</italic>
</td>
<td>615978</td>
</tr>
<tr><td> IFN-γ receptor 2 deficiency</td>
<td>Mutation in <italic>IFNGR2</italic>
: IFN-γR accessory chain<break></break>
147569</td>
<td>AR</td>
<td>M + L</td>
<td>IFN-γ signaling</td>
<td>Susceptibility to <italic>Mycobacteria</italic>
 and <italic>Salmonella</italic>
</td>
<td>614889</td>
</tr>
<tr><td> STAT1 deficiency (AD form)</td>
<td>Mutation in <italic>STAT1</italic>
 (lost of function)<break></break>
600555</td>
<td>AD</td>
<td>M + L</td>
<td>IFN-γsignaling</td>
<td>Susceptibility to <italic>Mycobacteria, Salmonella</italic>
</td>
<td>614892</td>
</tr>
<tr><td> Macrophage gp91 phox<break></break>
  deficiency</td>
<td>Mutation in <italic>CYBB</italic>
: Electron transport protein (gp 91 phox)<break></break>
300481</td>
<td>XL</td>
<td>Mϕ only</td>
<td>Killing (faulty<break></break>
O<sub>2</sub>
<sup>−</sup>
 production)</td>
<td>Isolated susceptibility to mycobacteria</td>
<td>300645</td>
</tr>
<tr><td> IRF8-deficiency (AD form)</td>
<td>Mutation in <italic>IRF8</italic>
: IL12 production by CD1c<sup>+</sup>
 MDC<break></break>
601565</td>
<td>AD</td>
<td>CD1c + MDC</td>
<td>Differentiation of CD1c + MDC subgroup</td>
<td>Susceptibility to <italic>Mycobacteria</italic>
</td>
<td>614893</td>
</tr>
<tr><td> Tyk2 deficiency</td>
<td>Mutation in <italic>TYK2</italic>
<break></break>
176941</td>
<td>AR</td>
<td>Normal, but<break></break>
Multiple cytokine signaling defect</td>
<td>Normal</td>
<td>Susceptibility to intracellular bacteria (Mycobacteria, Salmonella), fungi and viruses<break></break>
(+/−) Elevated IgE</td>
<td>611521</td>
</tr>
<tr><td> ISG15 deficiency</td>
<td>Mutation in <italic>ISG15</italic>
<break></break>
147571</td>
<td>AR</td>
<td></td>
<td>IFNγ defect production</td>
<td>Susceptibility to Mycobacteria (BCG)<break></break>
Brain calcification</td>
<td>616126</td>
</tr>
<tr><td> RORc deficiency</td>
<td>Mutation in <italic>RORC</italic>
<break></break>
602943</td>
<td>AR</td>
<td>L + NK</td>
<td>lack of functional RORγT protein :<break></break>
IFNγ defect production<break></break>
complete absence of IL-17A/F-producing T cells</td>
<td>mycobacteriosis and candidiasis</td>
<td>Not yet assigned</td>
</tr>
<tr><td colspan="7">2. Epidermodysplasia verruciformis</td>
</tr>
<tr><td> EVER1 deficiency</td>
<td>Mutations of <italic>TMC6</italic>
<break></break>
605828</td>
<td>AR</td>
<td>Keratinocytes and leukocytes</td>
<td>EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes</td>
<td>HPV (group B1) infections and cancer of the skin (typical EV)</td>
<td>226400</td>
</tr>
<tr><td> EVER2 deficiency</td>
<td>Mutations of <italic>TMC8</italic>
<break></break>
605829</td>
<td>AR</td>
<td>Keratinocytes and leukocytes</td>
<td>EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes</td>
<td>HPV (group B1) infections and cancer of the skin (typical EV)</td>
<td>226400</td>
</tr>
<tr><td> WHIM (Warts, Hypogammaglo-bulinemia, infections, Myelokathexis) syndrome</td>
<td>Gain-of-function mutations of <italic>CXCR4</italic>
, the receptor for CXCL12<break></break>
162643</td>
<td>AD</td>
<td>Granulocytes + Lymphocytes</td>
<td>Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1)</td>
<td>warts/Human Papilloma virus (HPV) infection<break></break>
Neutropenia<break></break>
Reduced B cell number<break></break>
Hypogammaglobulinemia</td>
<td>193670</td>
</tr>
<tr><td colspan="7">4. Predisposition to severe viral infection</td>
</tr>
<tr><td> STAT1 deficiency</td>
<td>Mutations of <italic>STAT1</italic>
<break></break>
600555</td>
<td>AR</td>
<td>T and NK cells and monocytes</td>
<td>STAT1-dependent<break></break>
IFN-α, and -β response</td>
<td>Severe viral infections<break></break>
Mycobacterial infection</td>
<td>613796</td>
</tr>
<tr><td> STAT2 deficiency</td>
<td>Mutations of <italic>STAT2</italic>
<break></break>
600556</td>
<td>AR</td>
<td>T and NK cells</td>
<td>STAT2-dependent IFN-α, and -β response</td>
<td>Severe viral infections<break></break>
(disseminated vaccine-strain measles)</td>
<td>Not yet assigned</td>
</tr>
<tr><td> IRF7 deficiency</td>
<td>Mutation in <italic>IRF7</italic>
<break></break>
605047</td>
<td>AR</td>
<td>Leukocytes and plasmacytoid dendritic cells,<break></break>
Non-hematopoietic cells</td>
<td>IFN-α, and -β production<break></break>
IFN-λ production</td>
<td>Severe influenza disease</td>
<td>Not yet assigned</td>
</tr>
<tr><td> CD16 deficiency</td>
<td>Mutation in CD16<break></break>
146740</td>
<td>AR</td>
<td>NK cells</td>
<td>Deficient spontaneous NK cell cytotoxicity</td>
<td>Susceptibility to severe viral infections, inc. HSV, EBV, HPV</td>
<td>615707</td>
</tr>
<tr><td colspan="7">5. Herpes simplex encephalitis (HSE)</td>
</tr>
<tr><td> TLR3 deficiency</td>
<td>(b) Mutations of <italic>TLR3</italic>
<break></break>
603029</td>
<td>AD<break></break>
AR</td>
<td>Central nervous system (CNS) resident cells and fibroblasts</td>
<td>TLR3-dependent<break></break>
IFN-α, -β, and -λ induction</td>
<td>Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here)</td>
<td>613002</td>
</tr>
<tr><td> UNC93B1 deficiency</td>
<td>(a) Mutations of <italic>UNC93B1</italic>
<break></break>
608204</td>
<td>AR</td>
<td>CNS resident cells and fibroblasts</td>
<td>UNC-93B-dependent<break></break>
IFN-α, -β, and -λ induction</td>
<td>Herpes simplex virus 1 encephalitis</td>
<td>610551</td>
</tr>
<tr><td> TRAF3 deficiency</td>
<td>(c) Mutations of <italic>TRAF3</italic>
<break></break>
601896</td>
<td>AD</td>
<td>CNS resident cells and fibroblasts</td>
<td>TRAF3-dependent<break></break>
IFN-α, -β, and -λ induction</td>
<td>Herpes simplex virus 1 encephalitis</td>
<td>614849</td>
</tr>
<tr><td> TRIF deficiency</td>
<td>(c) Mutations of <italic>TRIF, also called TICAM1</italic>
<break></break>
607601</td>
<td>AD<break></break>
AR</td>
<td>CNS resident cells and fibroblasts</td>
<td>TRIF-dependent<break></break>
IFN-α, -β, and -λ induction</td>
<td>Herpes simplex virus 1 encephalitis</td>
<td>614850</td>
</tr>
<tr><td> TBK1 deficiency</td>
<td>(c) Mutations of <italic>TBK1</italic>
<break></break>
604834</td>
<td>AD</td>
<td>CNS resident cells and fibroblasts</td>
<td>TBK1-dependent<break></break>
IFN-α, -β, and -λ induction</td>
<td>Herpes simplex virus 1 encephalitis</td>
<td>Not yet assigned</td>
</tr>
<tr><td colspan="7">6. Predisposition to invasive fungal diseases</td>
</tr>
<tr><td> CARD9 deficiency</td>
<td>Mutations of <italic>CARD9</italic>
<break></break>
607212</td>
<td>AR</td>
<td>Mononuclear phagocytes</td>
<td>CARD9 signaling pathway</td>
<td>Invasive candidiasis infection<break></break>
Deep dermatophytoses</td>
<td>212050</td>
</tr>
<tr><td colspan="7">7. Chronic mucocutaneous candidiasis (CMC)</td>
</tr>
<tr><td> IL-17RA deficiency</td>
<td>(a) Mutations in <italic>IL17RA</italic>
<break></break>
605461</td>
<td>AR</td>
<td>Epithelial cells, fibroblasts, mononuclear phagocytes</td>
<td>IL-17RA signaling pathway</td>
<td>CMC<break></break>
Folliculitis</td>
<td>613953</td>
</tr>
<tr><td> IL-17RC deficiency</td>
<td>Mutations in IL17RC<break></break>
610925</td>
<td>AR</td>
<td>Epithelial cells, fibroblasts, mononuclear phagocytes</td>
<td>IL-17RC signaling pathway</td>
<td>CMC</td>
<td>Not yet assigned</td>
</tr>
<tr><td> IL-17F deficiency</td>
<td>(b) Mutations in <italic>IL17F</italic>
<break></break>
606496</td>
<td>AD</td>
<td>T cells</td>
<td>IL-17 F-containing dimers</td>
<td>CMC<break></break>
Folliculitis</td>
<td>613956</td>
</tr>
<tr><td> STAT1 gain-of-function</td>
<td>(c) gain-of-function mutations in <italic>STAT1</italic>
<break></break>
600555</td>
<td>AD</td>
<td>T cells, B cells, monocytes</td>
<td>Gain-of-function STAT1 mutations that impair the development of IL-17-producing T cells</td>
<td>CMC<break></break>
Various fungal, bacterial and viral (HSV) infections<break></break>
Auto-immunity (Thyroiditis, diabetes, cytopenia)<break></break>
Enteropathy</td>
<td>614162</td>
</tr>
<tr><td> ACT1 deficiency</td>
<td>(c) Mutations in <italic>ACT1,</italic>
 also called <italic>TRAF3IP2</italic>
<break></break>
(607043)</td>
<td>AR</td>
<td>T cells, fibroblasts</td>
<td>Fibroblasts fail to respond to IL-17A and IL-17 F, and their T cells to IL-17E</td>
<td>CMC<break></break>
Blepharitis, Folliculitis and macroglossia</td>
<td>615527</td>
</tr>
<tr><td colspan="7">8. TLR signaling pathway deficiency</td>
</tr>
<tr><td> IRAK-4 deficiency</td>
<td>Mutations of <italic>IRAK4</italic>
, a component of TLR- and IL-1R-signaling pathway<break></break>
606883</td>
<td>AR</td>
<td>Lymphocytes + Granulocytes + Monocytes</td>
<td>TIR-IRAK signaling pathway</td>
<td>Bacterial infections (pyogens)</td>
<td>607676</td>
</tr>
<tr><td> MyD88 deficiency</td>
<td>Mutations of <italic>MYD88</italic>
, a component of the TLR and IL-1R signaling pathway<break></break>
602170</td>
<td>AR</td>
<td>Lymphocytes + Granulocytes + Monocytes</td>
<td>TIR-MyD88 signaling pathway</td>
<td>Bacterial infections (pyogens)</td>
<td>612260</td>
</tr>
<tr><td>9. Isolated congenital asplenia (ICA)</td>
<td>Mutations in <italic>RPSA</italic>
<break></break>
150370</td>
<td>AD</td>
<td>Spleen</td>
<td>RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome</td>
<td>Bacteremia (encapsulated bacteria)<break></break>
No spleen</td>
<td>271400</td>
</tr>
<tr><td>8. Trypanosomiasis</td>
<td>Mutations in <italic>APOL- I</italic>
 603743</td>
<td>AD</td>
<td></td>
<td>APOL-I</td>
<td>Trypanosomiasis</td>
<td>Not yet assigned</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>Total no. of gene defects in Table <xref rid="Tab6" ref-type="table">6</xref>
: 32</p>
<p>New genes added : <italic>RORC, IRF7, IL17RC, APOL-1</italic>
</p>
<p><italic>XL</italic>
 X-linked inheritance, <italic>AR</italic>
 autosomal recessive inheritance, <italic>AD</italic>
 autosomal dominant inheritance, <italic>NF-κB</italic>
 nuclear factor Kappa B, <italic>TIR</italic>
 Toll and Interleukin 1 Receptor, <italic>IFN</italic>
 interferon, <italic>HVP</italic>
 human papilloma virus, <italic>TLR</italic>
 Toll-like receptor, <italic>IL</italic>
 interleukin</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="Tab7"><label>Table 7</label>
<caption><p>Autoinflammatory disorders</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th>Disease</th>
<th>Genetic defect/<break></break>
Presumed pathogenesis<break></break>
OMIN gene</th>
<th>Inheritance</th>
<th>Affected cells</th>
<th>Functional defects</th>
<th>Associated Features</th>
<th>Phenotype<break></break>
OMIM number</th>
</tr>
</thead>
<tbody><tr><td colspan="7">1. Defects effecting the inflammasome</td>
</tr>
<tr><td> Familial Mediterranean Fever</td>
<td>Mutations of <italic>MEFV (lead to gain of pyrin function, resulting in inappropriate IL-1β release)</italic>
<break></break>
608107</td>
<td>AR<break></break>
AD</td>
<td>Mature granulocytes, cytokine-activated monocytes.</td>
<td>Decreased production of pyrin permits ASC-induced IL-1 processing and inflammation following subclinical serosal injury; macrophage apoptosis decreased.</td>
<td>Recurrent fever, serositis and inflammation responsive to colchicine. Predisoposes to vasculitis and inflammatory bowel disease.</td>
<td>249100<break></break>
134610</td>
</tr>
<tr><td> Mevalonate kinase deficiency (Hyper IgD syndrome)</td>
<td>Mutations of <italic>MVK (lead to a block in the mevalonate pathway. Interleukin-1beta mediates the inflammatory phenotype)</italic>
<break></break>
251170</td>
<td>AR</td>
<td></td>
<td>affecting cholesterol synthesis; pathogenesis of disease unclear</td>
<td>Periodic fever and leukocytosis with high IgD levels</td>
<td>260920</td>
</tr>
<tr><td> Muckle-Wells syndrome</td>
<td>Mutations of <italic>NLRP3</italic>
 (also called <italic>NALP3 CIAS1 or PYPAF1</italic>
) (<italic>lead to constitutive activation of the NLRP3 inflammasome)</italic>
<break></break>
606416</td>
<td><italic>AD</italic>
</td>
<td>PMNs Monocytes</td>
<td>Defect in cryopyrin, involved in leukocyte apoptosis and NFkB signaling and IL-1 processing</td>
<td>Urticaria, SNHL, amyloidosis.</td>
<td>191900</td>
</tr>
<tr><td> Familial cold autoinflammatory syndrome 1</td>
<td>Mutations of NLRP3 (See above)<break></break>
606416</td>
<td><italic>AD</italic>
</td>
<td><italic>PMNs, monocytes</italic>
</td>
<td>same as above</td>
<td>Non-pruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure.</td>
<td>120100</td>
</tr>
<tr><td> Familial cold<break></break>
autoinflammatory syndrome 2</td>
<td>Mutations of NLRP12<break></break>
609648</td>
<td><italic>AD</italic>
</td>
<td><italic>PMNs, monocytes</italic>
</td>
<td>same as above</td>
<td>Non-pruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure.</td>
<td>611762</td>
</tr>
<tr><td> Neonatal onset multisystem<break></break>
  inflammatory disease<break></break>
  (NOMID) or chronic infantile<break></break>
  neurologic cutaneous and<break></break>
  articular syndrome (CINCA)</td>
<td>Mutations of NLRP3<break></break>
CIAS1 (See above)<break></break>
606416</td>
<td><italic>AD</italic>
</td>
<td><italic>PMNs, chondrocytes</italic>
</td>
<td>same as above</td>
<td>Neonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation<italic>.</italic>
</td>
<td>607115</td>
</tr>
<tr><td> NLRC4-MAS (macrophage activating syndrome)<break></break>
 Familial cold<break></break>
  autoinflammatory syndrome 4</td>
<td>Mutation in NLRC4 (see functional defect)<break></break>
606831</td>
<td><italic>AD</italic>
</td>
<td><italic>PMNs monocytes macrophages</italic>
</td>
<td>Gain of function mutation in NLRC4 results in elevated secretion of IL-1β and IL-18 as well as macrophage activation</td>
<td>Severe enterocolitis and macrophage activation syndrome</td>
<td>616050<break></break>
616115</td>
</tr>
<tr><td> PLAID (PLCγ2 associated antibody deficiency and immune dysregulation)<break></break>
 Familial cold<break></break>
  autoinflammatory syndrome 3</td>
<td>Mutation in <italic>PLCG2</italic>
 ((see functional defect)<break></break>
600220</td>
<td>AD</td>
<td>B cells, NK, Mast cells</td>
<td>Mutations cause activation of IL-1 pathways</td>
<td>Cold urticaria hypogammaglobulinemia</td>
<td>614468</td>
</tr>
<tr><td> APLAID (autoinflammation and PLCγ2 associated antibody deficiency and immune dysregulation)</td>
<td>Mutation (c2120C > A) in PLCG2 (see function defect)<break></break>
600220</td>
<td>AD</td>
<td>B cells, NK, mast cells</td>
<td>The mutation leads to activation of the NLRP3 inflammasome (not provoked by cold temperature)</td>
<td>Blistering skin lesion, pulmonary and bowel disease</td>
<td>614878</td>
</tr>
<tr><td colspan="7">2. Non inflammasome-related conditions</td>
</tr>
<tr><td> (TNF receptor-associated<break></break>
 periodic syndrome (TRAPS)</td>
<td>Mutations of <italic>TNFRSF1A</italic>
 (resulting in increased TNF inflammatory signaling)<break></break>
191190</td>
<td>AD</td>
<td>PMNs, monocytes</td>
<td>Mutations of 55-kD TNF receptor leading to intracellular receptor retention or diminished soluble cytokine receptor available to bind TNF</td>
<td>Recurrent fever, serositis, rash, and ocular or joint inflammation</td>
<td>142680</td>
</tr>
<tr><td> Pyogenic sterile arthritis,<break></break>
  pyoderma gangrenosum,<break></break>
  acne (PAPA) syndrome</td>
<td>Mutations of <italic>PSTPIP1</italic>
 (also called <italic>C2BP1)</italic>
 (affects both pyrin and protein tyrosine phosphatase to regulate innate and adaptive immune responses)<break></break>
606347</td>
<td>AD</td>
<td>Hematopoietic tissues, upregulated in activated T-cells</td>
<td>Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response</td>
<td>Destructive arthritis, inflammatory skin rash, myositis</td>
<td>604416</td>
</tr>
<tr><td> Blau syndrome</td>
<td>Mutations of <italic>NOD2</italic>
 (also called CARD15) (involved in various inflammatory processes)<break></break>
605956</td>
<td>AD</td>
<td>Monocytes</td>
<td>Mutations in nucleotide binding site of CARD15, possibly disrupting interactions with lipopolysaccharides and NF-κB signaling</td>
<td>Uveitis, granulomatous synovitis, camptodactyly, rash and cranial neuropathies, 30 % develop Crohn’s disease</td>
<td>186580</td>
</tr>
<tr><td> ADAM17 deletion</td>
<td>Mutation in <italic>ADAM17</italic>
 (leads to tumor necrosis factor α converting enzyme deficiency)<break></break>
603639</td>
<td>AR</td>
<td>Leukocytes and epithelial cells</td>
<td>Defective TNFα production</td>
<td>Early onset diarrhea and skin lesions</td>
<td>614328</td>
</tr>
<tr><td> Chronic recurrent multifocal osteomyelitis and congenital<break></break>
  dyserythropoietic anemia<break></break>
  (Majeed syndrome)</td>
<td>Mutations of <italic>LPIN2</italic>
 (increased expression of the proinflammatory genes)<break></break>
605519</td>
<td>AR</td>
<td>Neutrophils, bone marrow cells</td>
<td>undefined</td>
<td>Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders</td>
<td>609628</td>
</tr>
<tr><td> DIRA (Deficiency of the<break></break>
  Interleukin 1 Receptor<break></break>
  Antagonist)</td>
<td>Mutations of <italic>IL1RN</italic>
 (see functional defect)<break></break>
147679</td>
<td>AR</td>
<td>PMNs, Monocytes</td>
<td>Mutations in the IL1 receptor antagonist allow unopposed action of Interleukin 1</td>
<td>Neonatal onset of sterile multifocal osteomyelitis, periostitis and pustulosis.</td>
<td>612852</td>
</tr>
<tr><td> DITRA – Deficiency of IL-36 receptor antagonist</td>
<td>Mutation in <italic>IL36RN</italic>
 (see functional defect)<break></break>
605507</td>
<td>AR</td>
<td>Keratinocyte Leukocytes</td>
<td>Mutations in IL-36RN leads to increase IL-8 production</td>
<td>Pustular Psoriasis</td>
<td>614204</td>
</tr>
<tr><td> SLC29A3 mutation</td>
<td>Mutation in <italic>SLC29A3</italic>
<break></break>
612373</td>
<td>AR</td>
<td>Leukocyte, bone cells</td>
<td>Hyperpigmentation hypertrichosis</td>
<td>Histiocytosis-lymphadenopathy plus syndrome</td>
<td>602782</td>
</tr>
<tr><td> CAMPS (CARD14 mediated psoriasis)</td>
<td>Mutation in <italic>CARD14</italic>
 (see functional defect)<break></break>
607211</td>
<td>AD</td>
<td>Mainly in Keratinocyte</td>
<td>Mutations in CARD14 activate the NF-<italic>k</italic>
B pathway and production of IL-8</td>
<td>Psoriasis</td>
<td>602723</td>
</tr>
<tr><td> Cherubism</td>
<td>Mutation in <italic>SH3BP2</italic>
 (see functional defect)<break></break>
602104</td>
<td>AD</td>
<td>Stroma cells, bone cells</td>
<td>Hyperactived macrophage and increase NF-kB</td>
<td>Bone degeneration in jaws</td>
<td>118400</td>
</tr>
<tr><td> CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy)</td>
<td>Mutation in <italic>PSMB8</italic>
,<break></break>
(see functional defect)<break></break>
177046</td>
<td>AR</td>
<td>Keratinocyte, B cell adipose cells</td>
<td>Mutations cause increase IL-6 production</td>
<td>Dystrophy, panniculitis</td>
<td>256040</td>
</tr>
<tr><td> COPA defect</td>
<td>Mutation in COPA (Coatamer protein complex, subunit alpha)</td>
<td>AD</td>
<td>PMNs and tissues specific cells</td>
<td>Mutant COPA leads to defective intracellular transport via the coat protein complex I (COPI)</td>
<td>Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production</td>
<td>601924</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>Total no. of gene defects in Table <xref rid="Tab7" ref-type="table">7</xref>
: 17</p>
<p>New genes added: <italic>NLRC4, ADAM17, COPA</italic>
</p>
<p>Notes: Autoinflammatory diseases are clinical disorders marked by abnormally increased inflammation, mediated predominantly by the cells and molecules of the innate immune system, with a significant host predisposition. While the genetic defect of one of the most common autoinflammatory conditions, PFAPA, is not known, recent studies suggest that it is associated with activation of IL-1 pathway and response to IL-1beta antagonists</p>
<p>Muckle-Wells syndrome, familial cold autoinflammatory syndrome and neonatal onset multisystem inflammatory disease (NOMID) which is also called chronic infantile neurologic cutaneous and articular syndrome (CINCA) are caused by similar mutations in <italic>CIAS1/NLRP3</italic>
 mutations. The disease phenotype in any individual appears to depend on modifying effects of other genes and environmental factors</p>
<p><italic>AR</italic>
 autosomal recessive inheritance, <italic>AD</italic>
 autosomal dominant inheritance, <italic>PMN</italic>
 polymorphonuclear cells, <italic>ASC</italic>
 apoptosis-associated speck-like protein with a caspase recruitment domain, <italic>CARD</italic>
 caspase recruitment domain, <italic>CD2BP1</italic>
 CD2 binding protein-1, <italic>PSTPIP1</italic>
 Proline/serine/threonine phosphatase-interacting protein 1, <italic>SNHL</italic>
 sensorineural hearing loss, <italic>CIAS1</italic>
 cold-induced autoinflammatory syndrome 1</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="Tab8"><label>Table 8</label>
<caption><p>Complement deficiencies</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th>Disease</th>
<th>Genetic defect; presumed pathogenesis<break></break>
OMIM gene</th>
<th>Inheritance</th>
<th>Laboratory features</th>
<th>Associated Features</th>
<th>Phenotype<break></break>
OMIM number</th>
</tr>
</thead>
<tbody><tr><td colspan="6">1) Integral complement cascade component deficiencies</td>
</tr>
<tr><td> C1q deficiency</td>
<td><italic>C1QA,</italic>
: Classical complement pathway component<break></break>
120550</td>
<td>AR</td>
<td>Absent CH50 hemolytic activity, Defective activation of the classical pathway<break></break>
Diminished clearance of apoptotic cells</td>
<td>SLE, infections with encapsulated organisms</td>
<td>613652</td>
</tr>
<tr><td> C1q deficiency</td>
<td><italic>C1QB:</italic>
 Classical complement pathway component<break></break>
120570</td>
<td>AR</td>
<td>Absent CH50 hemolytic activity, Defective activation of the classical pathway<break></break>
Diminished clearance of apoptotic cells</td>
<td>SLE, infections with encapsulated organisms</td>
<td>613652</td>
</tr>
<tr><td> C1q deficiency</td>
<td><italic>C1QC:</italic>
 Classical complement pathway component<break></break>
120575</td>
<td>AR</td>
<td>Absent CH50 hemolytic activity, Defective activation of the classical pathway<break></break>
Diminished clearance of apoptotic cells</td>
<td>SLE, infections with encapsulated organisms</td>
<td>613652</td>
</tr>
<tr><td> C1r deficiency</td>
<td><italic>C1R</italic>
: Classical complement pathway component<break></break>
613785</td>
<td>AR</td>
<td>Absent CH50 hemolytic activity, Defective activation of the classical pathway</td>
<td>SLE, infections with encapsulated organisms</td>
<td>216950</td>
</tr>
<tr><td> C1s deficiency</td>
<td><italic>C1S</italic>
: Classical complement pathway component<break></break>
120580</td>
<td>AR</td>
<td>Absent CH50 hemolytic activity<break></break>
Defective activation of the classical pathway</td>
<td>SLE, infections with encapsulated organisms</td>
<td>613783</td>
</tr>
<tr><td> C4 deficiency</td>
<td><italic>C4A,</italic>
 Classical complement pathway components<break></break>
120810</td>
<td>AR</td>
<td>Absent CH50 hemolytic activity, Defective activation of the classical pathway<break></break>
Complete deficiency requires biallelic mutations/deletions/conversions of both C4A and C4B</td>
<td>SLE, infections with encapsulated organisms</td>
<td>614380</td>
</tr>
<tr><td> C4 deficiency</td>
<td><italic>C4B</italic>
: Classical complement pathway components<break></break>
120820</td>
<td>AR</td>
<td>Absent CH50 hemolytic activity, Defective activation of the classical pathway<break></break>
Complete deficiency requires biallelic mutations/deletions/conversions of both C4A and C4B</td>
<td>SLE, infections with encapsulated organisms</td>
<td>614379</td>
</tr>
<tr><td> C2 deficiency</td>
<td><italic>C2</italic>
: Classical complement pathway component<break></break>
217000</td>
<td>AR</td>
<td>Absent CH50 hemolytic activity, Defective activation of the classical pathway</td>
<td>SLE, infections with encapsulated organisms, atherosclerosis</td>
<td>613927</td>
</tr>
<tr><td> C3 deficiency<break></break>
LOF</td>
<td><italic>C3</italic>
: Central complement component<break></break>
120700</td>
<td>AR</td>
<td>Absent CH50 and AH50 hemolytic activity<break></break>
Defective opsonization<break></break>
Defective humoral immune response</td>
<td>Infections; glomerulonephritis;<break></break>
Atypical Hemolytic-uremic syndrome with gain-of-function mutations.</td>
<td>613779</td>
</tr>
<tr><td> C3 GOF</td>
<td><italic>C3</italic>
: Central complement component<break></break>
120700</td>
<td>Gain-of-function AD</td>
<td>Increased activation of complement</td>
<td>Atypical Hemolytic-uremic syndrome</td>
<td>612925</td>
</tr>
<tr><td> C5 deficiency</td>
<td><italic>C5</italic>
: Terminal complement component<break></break>
120900</td>
<td>AR</td>
<td>Absent CH50 and AH50 hemolytic activity<break></break>
Defective bactericidal activity</td>
<td>Neisserial infections</td>
<td>609536</td>
</tr>
<tr><td> C6 deficiency</td>
<td><italic>C6</italic>
: Terminal complement component<break></break>
217050</td>
<td>AR</td>
<td>Absent CH50 and AH50 hemolytic activity<break></break>
Defective bactericidal activity</td>
<td>Neisserial infections</td>
<td>612446</td>
</tr>
<tr><td> C7 deficiency</td>
<td><italic>C7</italic>
: Terminal complement component<break></break>
217070</td>
<td>AR</td>
<td>Absent CH50 and AH50 hemolytic activity<break></break>
Defective bactericidal activity</td>
<td>Neisserial infections</td>
<td>610102</td>
</tr>
<tr><td> C8 αdeficiency</td>
<td><italic>C8A</italic>
: Terminal complement component<break></break>
120950</td>
<td>AR</td>
<td>Absent CH50 and AH50 hemolytic activity<break></break>
Defective bactericidal activity</td>
<td>Neisserial infections</td>
<td>613790</td>
</tr>
<tr><td> C8γ deficiency</td>
<td><italic>C8G:</italic>
 Terminal complement component<break></break>
120930</td>
<td>AR</td>
<td>Absent CH50 and AH50 hemolytic activity<break></break>
Defective bactericidal activity</td>
<td>Neisserial infections</td>
<td>613790</td>
</tr>
<tr><td> C8β deficiency</td>
<td><italic>C8B</italic>
: Terminal complement component<break></break>
120960</td>
<td>AR</td>
<td>Absent CH50 and AH50 hemolytic activity<break></break>
Defective bactericidal activity</td>
<td>Neisserial infections</td>
<td>613789</td>
</tr>
<tr><td> C9 deficiency</td>
<td><italic>C9</italic>
: Terminal complement component<break></break>
120940</td>
<td>AR</td>
<td>Reduced CH50 and AP50 hemolytic activity<break></break>
Deficient bactericidal activity</td>
<td>Mild susceptibility to Neisserial infections</td>
<td>613825</td>
</tr>
<tr><td> MASP2 deficiency</td>
<td><italic>MASP2</italic>
: Cleavage of C4<break></break>
605102</td>
<td>AR</td>
<td>Deficient activation of the lectin activation pathway</td>
<td>Pyogenic infections;<break></break>
Inflammatory lung disease, autoimmunity</td>
<td>613791</td>
</tr>
<tr><td> Ficolin 3 deficiency</td>
<td><italic>FCN3:</italic>
 Activates the classical complement pathway<break></break>
604973</td>
<td>AR</td>
<td>Absence of complement activation by the Ficolin 3 pathway.</td>
<td>Respiratory infections, abscesses</td>
<td>613860</td>
</tr>
<tr><td colspan="6">2) Complement Regulatory defects</td>
</tr>
<tr><td> C1 inhibitor deficiency</td>
<td><italic>SERPING1</italic>
: regulation of kinins and complement activation<break></break>
606860</td>
<td>AD</td>
<td>Spontaneous activation of the complement pathway with consumption of C4/C2<break></break>
Spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen</td>
<td>Hereditary angioedema</td>
<td>106100</td>
</tr>
<tr><td> Factor B</td>
<td><italic>CFB:</italic>
 Activation of the alternative pathway<break></break>
138470</td>
<td>AD</td>
<td>Gain-of-function mutation with increased spontaneous AH50</td>
<td>aHUS</td>
<td>612924</td>
</tr>
<tr><td> Factor D deficiency</td>
<td><italic>CFD</italic>
: Regulation of the alternative complement pathway<break></break>
134350</td>
<td>AR</td>
<td>Absent AH50 hemolytic activity</td>
<td>Neisserial infections</td>
<td>613912</td>
</tr>
<tr><td> Properdin deficiency</td>
<td><italic>CFP</italic>
: Regulation of the alternative complement pathway<break></break>
300383</td>
<td>XL</td>
<td>Absent AH50 hemolytic activity</td>
<td>Neisserial infections</td>
<td>312060</td>
</tr>
<tr><td> Factor I deficiency</td>
<td><italic>CFI</italic>
: Regulation of the alternative complement pathway<break></break>
217030</td>
<td>AR</td>
<td>Spontaneous activation of the alternative complement pathway with consumption of C3</td>
<td>Infections, Neisserial infections, aHUS, preeclampsia</td>
<td>610984<break></break>
612923</td>
</tr>
<tr><td> Factor H deficiency</td>
<td><italic>CFH</italic>
: Regulation of the alternative complement pathway<break></break>
134370</td>
<td>AR/AD</td>
<td>Spontaneous activation of the alternative complement pathway with consumption of C3</td>
<td>Infections, Neisserial infections, aHUS, preeclampsia</td>
<td>609814<break></break>
235400</td>
</tr>
<tr><td> Factor H –related protein deficiencies</td>
<td><italic>CFHR1-5</italic>
: Bind C3b<break></break>
134371<break></break>
600889<break></break>
605336<break></break>
605337<break></break>
608593</td>
<td>AR/AD</td>
<td>Normal CH50, AH50, autoantibodies to Factor H. Linked deletions of one or more CFHR genes leads to susceptibility autoantibody-mediated aHUS</td>
<td>aHUS, Neisserial infections</td>
<td>235400</td>
</tr>
<tr><td> Thrombomodulin</td>
<td><italic>THBD</italic>
: Regulates complement and coagulant activation<break></break>
188040</td>
<td>AD</td>
<td>Normal CH50, AH50</td>
<td>aHUS</td>
<td>612926</td>
</tr>
<tr><td> Complement Receptor 3 (CR3) deficiency</td>
<td><italic>ITGAM</italic>
<break></break>
120980</td>
<td>AR</td>
<td>CR3 expression is lost in LAD1. See LAD1 in Table <xref rid="Tab5" ref-type="table">5</xref>
</td>
<td>Infections</td>
<td>609939</td>
</tr>
<tr><td> Membrane Cofactor Protein (CD46) deficiency</td>
<td><italic>CD46</italic>
: Dissociates C3b and C4b<break></break>
120920</td>
<td>AD</td>
<td>Inhibitor of complement alternate pathway, decreased C3b binding</td>
<td>aHUS, infections, preeclampsia</td>
<td>612922</td>
</tr>
<tr><td> Membrane Attack Complex Inhibitor (CD59) deficiency</td>
<td><italic>CD59:</italic>
 Regulates the membrane attack complex formation<break></break>
107271</td>
<td>AR</td>
<td>Erythrocytes highly susceptible to complement-mediated lysis</td>
<td>Hemolytic anemia, polyneuropathy</td>
<td>612300</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>Total no. of genes Tables <xref rid="Tab8" ref-type="table">8</xref>
 and <xref rid="Tab9" ref-type="table">9</xref>
: 30</p>
<p>No new genes added to the 2015 classification</p>
<p><italic>XL</italic>
 X-linked inheritance, <italic>AR</italic>
 autosomal recessive inheritance, <italic>AD</italic>
 autosomal dominant inheritance, <italic>MAC</italic>
 membrane attack complex, <italic>SLE</italic>
 systemic lupus erythematosus, <italic>MASP</italic>
 MBP associated serine protease 2</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="Tab9"><label>Table 9</label>
<caption><p>Phenocopies of PID</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th>Disease</th>
<th>Genetic defect/presumed pathogenesis</th>
<th>Circulating T cells</th>
<th>Circulating B cells</th>
<th>Serum Ig</th>
<th>Associated features/similar PID</th>
</tr>
</thead>
<tbody><tr><td colspan="6">Associated with somatic mutations</td>
</tr>
<tr><td> Autoimmune lymphoproliferative syndrome (ALPS–SFAS)</td>
<td>Somatic mutation in <italic>TNFRSF6</italic>
</td>
<td>Increased CD4−CD8−double negative (DN) T alpha/beta cells</td>
<td>Normal, but increased number of CD5+ B cells</td>
<td>Normal or increased</td>
<td>Splenomegaly, lymphadenopathy, autoimmune cytopenias<break></break>
Defective lymphocyte apoptosis/<italic>ALPS–FAS (=ALPS type Im)</italic>
</td>
</tr>
<tr><td> RAS-associated autoimmune leukoproliferative disease (RALD)</td>
<td>Somatic mutation in <italic>KRAS</italic>
 (gain-of-function)</td>
<td>Normal</td>
<td>B cell lymphocytosis</td>
<td>Normal or increased</td>
<td>Splenomegaly, lymphadenopathy, autoimmune cytopenias, granulocytosis, monocytosis/<italic>ALPS-like</italic>
</td>
</tr>
<tr><td> RAS-associated autoimmune leukoproliferative disease (RALD)</td>
<td>Somatic mutation in <italic>NRAS</italic>
 (gain-of-function)</td>
<td>Increased CD4−CD8−double negative (DN) T alpha/beta cells</td>
<td>Lymphocytosis</td>
<td></td>
<td>Splenomegaly, lymphadenopathy, autoantibodies/<italic>ALPS-like</italic>
</td>
</tr>
<tr><td> Cryopyrinopathy, (Muckle-Wells /CINCA/NOMID-like syndrome)</td>
<td>Somatic mutation in <italic>NLRP3</italic>
</td>
<td>Normal</td>
<td>Normal</td>
<td>Normal</td>
<td>Urticaria-like rash, arthropathy, neurological symptoms</td>
</tr>
<tr><td colspan="6">Associated with autoantibodies</td>
</tr>
<tr><td> Chronic mucocutaneous candidiasis (isolated or with APECED syndrome)</td>
<td>Germline mutation in <italic>AIRE</italic>
 AutoAb to IL-17 and/or IL-22</td>
<td>Normal</td>
<td>Normal</td>
<td>Normal</td>
<td>Endocrinopathy, chronic mucocutaneous candidiasis/<italic>CMC</italic>
</td>
</tr>
<tr><td> Adult-onset immunodeficiency</td>
<td>AutoAb to IFN gamma</td>
<td>Decreased naive T cells</td>
<td>Normal</td>
<td>Normal</td>
<td>Mycobacterial, fungal, <italic>Salmonella</italic>
 VZV infections/<italic>MSMD, or CID</italic>
</td>
</tr>
<tr><td> Recurrent skin infection</td>
<td>AutoAb to IL-6</td>
<td>Normal</td>
<td>Normal</td>
<td>Normal</td>
<td>Staphylococcal infections/<italic>STAT3 deficiency</italic>
</td>
</tr>
<tr><td> Pulmonary alveolar proteinosis</td>
<td>AutoAb to GM-CSF</td>
<td>Normal</td>
<td>Normal</td>
<td>Normal</td>
<td>Pulmonary alveolar proteinosis, cryptococcal meningitis/<italic>CSF2RA deficiency</italic>
</td>
</tr>
<tr><td> Acquired angioedema</td>
<td>AutoAb to CI inhibitor</td>
<td>Normal</td>
<td>Normal</td>
<td>Normal</td>
<td>Angioedema/<italic>C1 INH deficiency</italic>
 (hereditary angioedema)</td>
</tr>
<tr><td> Atypical Hemolytic Uremic Syndrome</td>
<td>AutoAb to Complement Factor H</td>
<td>Normal</td>
<td>Normal</td>
<td>Normal</td>
<td>aHUS<break></break>
Spontaneous activation of the alternative complement pathway</td>
</tr>
</tbody>
</table>
</table-wrap>
The classification this year differs in a number of ways from the previous edition published in 2014. Importantly, each defect is now listed in only one table. The diverse immunological phenotypes of many conditions imply that a very large number of conditions could very readily be listed in multiple tables. However, with the increasing number of identified defects, this would make each table large and cumbersome. For this reason, we chose to list each defect in one table only and to place it according to the most pronounced and fundamental defect. For this reason and as an example, CD40L deficiency is now found in Table <xref rid="Tab1" ref-type="table">1</xref>
 amongst combined immunodeficiencies, because CD40L is a T cell signaling molecule whose absence leads to both cellular and humoral defects, even though it was originally described as an antibody deficiency. Although some of our placements may be disputed, the committee came to these decisions after much thought and deliberation.</p>
<p>The title of Table <xref rid="Tab6" ref-type="table">6</xref>
 has now been slightly changed to ‘Defects in intrinsic and innate immunity’ and contains defects characterized by susceptibility to specific organisms. For this reason, the MSMDs (Mendelian Susceptibility to Mycobacterial Disease) are now in Table <xref rid="Tab6" ref-type="table">6</xref>
, having previously been in Table <xref rid="Tab5" ref-type="table">5</xref>
 (Phagocytic Disorders).</p>
<p>In previous editions, we have placed an asterisk against conditions in which 10 or fewer individuals had been described in the literature. However, this is now felt to be an artificial indicator as, once described, a condition may be found in additional patients but not necessarily reported. For this reason, there is no specific indicator of the number of patients identified or reported.</p>
<p>There is a growing appreciation of wide phenotypic variability for many of the individual specific gene defects, reflecting not only the variety of mutations within each gene but also host and/or environmental modifying factors that may impact the phenotype even between individuals with the same mutation within the same gene. The complexities of these conditions in terms of clinical and immunological presentation and heterogeneity cannot easily be captured in the limited space of a table format. For this reason, the furthest right column contains the Online Mendelian Inheritance in Man (OMIM) reference for each condition to allow access to a source of greater detail and updated information as to the phenotype.</p>
<p>A number of the new genes included in this edition of the classification tables are molecules associated not only with the immune system, but also with more generic cellular functions; such defects result in both immunological and non-immunological abnormalities. In addition, there are a number of gain-of-function (GOF) mutations identified such as in PIK3CD. In CARD11 and STAT1 for example, there are both autosomal dominant GOF and autosomal recessive loss of function variants and these different modes of inheritance in the same gene lead to different functional consequences and hence different immunological and clinical phenotypes. The other trend that is increasingly observed is the increase in disorder of immunedysregulation rather than pure immunodeficiency.</p>
<p>The goal of the IUIS Expert Committee on Primary Immunodeficiencies is to increase awareness, facilitate recognition and promote optimal treatment for patients with Primary Immunodeficiencies. In addition to the current report and previous ‘classification table’ publications, the committee has also produced a ‘Phenotypic Approach for IUIS PID classification and Diagnosis: Guidelines for Clinicians at the Bedside,’ which aims to lead physicians to particular groups of PIDs starting from clinical features and combining routine immunological investigations. This will be further updated to include the newly identified defects. Together these contributions will hopefully allow a practical clinical framework for PID diagnosis.</p>
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Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015

Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015

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