Delineation of 15q13.3 microdeletions
Identifieur interne : 005570 ( Istex/Corpus ); précédent : 005569; suivant : 005571Delineation of 15q13.3 microdeletions
Auteurs : A. Masurel-Paulet ; J. Andrieux ; P. Callier ; Jm Cuisset ; C. Le Caignec ; M. Holder ; C. Thauvin-Robinet ; B. Doray ; E. Flori ; Mp Alex-Cordier ; M. Beri ; O. Boute ; B. Delobel ; A. Dieux ; L. Vallee ; S. Jaillard ; S. Odent ; B. Isidor ; C. Beneteau ; J. Vigneron ; F. Bilan ; B. Gilbert-Dussardier ; C. Dubourg ; A. Labalme ; C. Bidon ; A. Gautier ; P. Pernes ; Jm Pinoit ; F. Huet ; F. Mugneret ; B. Aral ; P. Jonveaux ; D. Sanlaville ; L. FaivreSource :
- Clinical Genetics [ 0009-9163 ] ; 2010-08.
Abstract
Masurel‐Paulet A, Andrieux J, Callier P, Cuisset JM, Le Caignec C, Holder M, Thauvin‐Robinet C, Doray B, Flori E, Alex‐Cordier MP, Beri M, Boute O, Delobel B, Dieux A, Vallee L, Jaillard S, Odent S, Isidor B, Beneteau C, Vigneron J, Bilan F, Gilbert‐Dussardier B, Dubourg C, Labalme A, Gautier A, Pernes P, Bidon C, Pinoit JM, Huet F, Mugneret F, Aral B, Jonveaux P, Sanlaville D, Faivre L. Delineation of 15q13.3 microdeletions. The increasing use of array‐comparative genomic hybridization (array‐CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the CHRNA7 gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4–BP5 microdeletion out of a series of 4625 patients screened by array‐CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of CHRNA7 yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical ∼1.5 Mb BP4–BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the CHRNA7 gene.
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DOI: 10.1111/j.1399-0004.2010.01374.x
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Holder</name><affiliation><mods:affiliation>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</mods:affiliation></affiliation></author><author><name sortKey="Thauvin Obinet, C" sort="Thauvin Obinet, C" uniqKey="Thauvin Obinet C" first="C" last="Thauvin-Robinet">C. Thauvin-Robinet</name><affiliation><mods:affiliation>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon</mods:affiliation></affiliation></author><author><name sortKey="Doray, B" sort="Doray, B" uniqKey="Doray B" first="B" last="Doray">B. Doray</name><affiliation><mods:affiliation>Service de Génétique Médicale</mods:affiliation></affiliation></author><author><name sortKey="Flori, E" sort="Flori, E" uniqKey="Flori E" first="E" last="Flori">E. Flori</name><affiliation><mods:affiliation>Service de Cytogénétique, Hôpital Hautepierre, CHU, Strasbourg, France</mods:affiliation></affiliation></author><author><name sortKey="Alex Ordier, Mp" sort="Alex Ordier, Mp" uniqKey="Alex Ordier M" first="Mp" last="Alex-Cordier">Mp Alex-Cordier</name><affiliation><mods:affiliation>Service de Génétique, Hospices Civils de Lyon, Bron, France</mods:affiliation></affiliation></author><author><name sortKey="Beri, M" sort="Beri, M" uniqKey="Beri M" first="M" last="Beri">M. Beri</name><affiliation><mods:affiliation>Laboratoire de Génétique Médicale, Hôpital Brabois, CHU, Nancy, France</mods:affiliation></affiliation></author><author><name sortKey="Boute, O" sort="Boute, O" uniqKey="Boute O" first="O" last="Boute">O. Boute</name><affiliation><mods:affiliation>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</mods:affiliation></affiliation></author><author><name sortKey="Delobel, B" sort="Delobel, B" uniqKey="Delobel B" first="B" last="Delobel">B. Delobel</name><affiliation><mods:affiliation>Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Dieux, A" sort="Dieux, A" uniqKey="Dieux A" first="A" last="Dieux">A. Dieux</name><affiliation><mods:affiliation>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</mods:affiliation></affiliation></author><author><name sortKey="Vallee, L" sort="Vallee, L" uniqKey="Vallee L" first="L" last="Vallee">L. Vallee</name><affiliation><mods:affiliation>Service de Neuropédiatrie, CHRU, Lille</mods:affiliation></affiliation></author><author><name sortKey="Jaillard, S" sort="Jaillard, S" uniqKey="Jaillard S" first="S" last="Jaillard">S. Jaillard</name><affiliation><mods:affiliation>Service de Cytogénétique, CHU, Rennes, France</mods:affiliation></affiliation></author><author><name sortKey="Odent, S" sort="Odent, S" uniqKey="Odent S" first="S" last="Odent">S. Odent</name><affiliation><mods:affiliation>Unité de Génétique Médicale, Hôpital Sud, CHU, Rennes, France</mods:affiliation></affiliation></author><author><name sortKey="Isidor, B" sort="Isidor, B" uniqKey="Isidor B" first="B" last="Isidor">B. Isidor</name><affiliation><mods:affiliation>Service de Génétique Médicale, CHU, Nantes</mods:affiliation></affiliation></author><author><name sortKey="Beneteau, C" sort="Beneteau, C" uniqKey="Beneteau C" first="C" last="Beneteau">C. Beneteau</name><affiliation><mods:affiliation>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France</mods:affiliation></affiliation></author><author><name sortKey="Vigneron, J" sort="Vigneron, J" uniqKey="Vigneron J" first="J" last="Vigneron">J. Vigneron</name><affiliation><mods:affiliation>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France</mods:affiliation></affiliation></author><author><name sortKey="Bilan, F" sort="Bilan, F" uniqKey="Bilan F" first="F" last="Bilan">F. Bilan</name><affiliation><mods:affiliation>Service de Génétique, CHU, Poitiers, France</mods:affiliation></affiliation></author><author><name sortKey="Gilbert Ussardier, B" sort="Gilbert Ussardier, B" uniqKey="Gilbert Ussardier B" first="B" last="Gilbert-Dussardier">B. Gilbert-Dussardier</name><affiliation><mods:affiliation>Service de Génétique, CHU, Poitiers, France</mods:affiliation></affiliation></author><author><name sortKey="Dubourg, C" sort="Dubourg, C" uniqKey="Dubourg C" first="C" last="Dubourg">C. Dubourg</name><affiliation><mods:affiliation>Laboratoire de Génétique Moléculaire, CHU, Rennes, France</mods:affiliation></affiliation></author><author><name sortKey="Labalme, A" sort="Labalme, A" uniqKey="Labalme A" first="A" last="Labalme">A. Labalme</name><affiliation><mods:affiliation>Service de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, GHE, Lyon, France</mods:affiliation></affiliation></author><author><name sortKey="Bidon, C" sort="Bidon, C" uniqKey="Bidon C" first="C" last="Bidon">C. Bidon</name><affiliation><mods:affiliation>Biologie Moléculaire, Plateau Technique de Biologie, CHU le Bocage, Dijon, France</mods:affiliation></affiliation></author><author><name sortKey="Gautier, A" sort="Gautier, A" uniqKey="Gautier A" first="A" last="Gautier">A. Gautier</name><affiliation><mods:affiliation>Neuropédiatrie, CHU, Nantes, France</mods:affiliation></affiliation></author><author><name sortKey="Pernes, P" sort="Pernes, P" uniqKey="Pernes P" first="P" last="Pernes">P. Pernes</name><affiliation><mods:affiliation>Centre de soins Saint Exupery, Vendin Le Vieil, France</mods:affiliation></affiliation></author><author><name sortKey="Pinoit, Jm" sort="Pinoit, Jm" uniqKey="Pinoit J" first="Jm" last="Pinoit">Jm Pinoit</name><affiliation><mods:affiliation>Service de Pédopsychiatrie</mods:affiliation></affiliation></author><author><name sortKey="Huet, F" sort="Huet, F" uniqKey="Huet F" first="F" last="Huet">F. Huet</name><affiliation><mods:affiliation>Service de Pédiatrie, Hôpital d’Enfants, CHU, Dijon, France</mods:affiliation></affiliation></author><author><name sortKey="Mugneret, F" sort="Mugneret, F" uniqKey="Mugneret F" first="F" last="Mugneret">F. Mugneret</name><affiliation><mods:affiliation>Service de cytogénétique, Plateau Technique de Biologie, CHU Le Bocage, Dijon</mods:affiliation></affiliation></author><author><name sortKey="Aral, B" sort="Aral, B" uniqKey="Aral B" first="B" last="Aral">B. Aral</name><affiliation><mods:affiliation>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France</mods:affiliation></affiliation></author><author><name sortKey="Jonveaux, P" sort="Jonveaux, P" uniqKey="Jonveaux P" first="P" last="Jonveaux">P. Jonveaux</name><affiliation><mods:affiliation>Laboratoire de Génétique Médicale, Hôpital Brabois, CHU, Nancy, France</mods:affiliation></affiliation></author><author><name sortKey="Sanlaville, D" sort="Sanlaville, D" uniqKey="Sanlaville D" first="D" last="Sanlaville">D. Sanlaville</name><affiliation><mods:affiliation>Service de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, GHE, Lyon, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Biologie Moléculaire, Plateau Technique de Biologie, CHU le Bocage, Dijon, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Neuropédiatrie, CHU, Nantes, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Centre de soins Saint Exupery, Vendin Le Vieil, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Service de Pédopsychiatrie</mods:affiliation></affiliation><affiliation><mods:affiliation>Service de Pédiatrie, Hôpital d’Enfants, CHU, Dijon, France</mods:affiliation></affiliation><affiliation><mods:affiliation>EA 4171, Université Claude Bernard Lyon 1, Lyon, France</mods:affiliation></affiliation></author><author><name sortKey="Faivre, L" sort="Faivre, L" uniqKey="Faivre L" first="L" last="Faivre">L. Faivre</name><affiliation><mods:affiliation>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: laurence.faivre@chu‐dijon.fr</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:B66C60804B18AC075AB8BC4FD727A1408605E2AD</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1111/j.1399-0004.2010.01374.x</idno><idno type="url">https://api.istex.fr/document/B66C60804B18AC075AB8BC4FD727A1408605E2AD/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">005570</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">005570</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main">Delineation of 15q13.3 microdeletions</title><author><name sortKey="Masurel Aulet, A" sort="Masurel Aulet, A" uniqKey="Masurel Aulet A" first="A" last="Masurel-Paulet">A. Masurel-Paulet</name><affiliation><mods:affiliation>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon</mods:affiliation></affiliation></author><author><name sortKey="Andrieux, J" sort="Andrieux, J" uniqKey="Andrieux J" first="J" last="Andrieux">J. Andrieux</name><affiliation><mods:affiliation>Laboratoire de Génétique Médicale, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</mods:affiliation></affiliation></author><author><name sortKey="Callier, P" sort="Callier, P" uniqKey="Callier P" first="P" last="Callier">P. Callier</name><affiliation><mods:affiliation>Service de cytogénétique, Plateau Technique de Biologie, CHU Le Bocage, Dijon</mods:affiliation></affiliation></author><author><name sortKey="Cuisset, Jm" sort="Cuisset, Jm" uniqKey="Cuisset J" first="Jm" last="Cuisset">Jm Cuisset</name><affiliation><mods:affiliation>Service de Neuropédiatrie, CHRU, Lille</mods:affiliation></affiliation></author><author><name sortKey="Le Caignec, C" sort="Le Caignec, C" uniqKey="Le Caignec C" first="C" last="Le Caignec">C. Le Caignec</name><affiliation><mods:affiliation>Service de Génétique Médicale, CHU, Nantes</mods:affiliation></affiliation></author><author><name sortKey="Holder, M" sort="Holder, M" uniqKey="Holder M" first="M" last="Holder">M. Holder</name><affiliation><mods:affiliation>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</mods:affiliation></affiliation></author><author><name sortKey="Thauvin Obinet, C" sort="Thauvin Obinet, C" uniqKey="Thauvin Obinet C" first="C" last="Thauvin-Robinet">C. Thauvin-Robinet</name><affiliation><mods:affiliation>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon</mods:affiliation></affiliation></author><author><name sortKey="Doray, B" sort="Doray, B" uniqKey="Doray B" first="B" last="Doray">B. Doray</name><affiliation><mods:affiliation>Service de Génétique Médicale</mods:affiliation></affiliation></author><author><name sortKey="Flori, E" sort="Flori, E" uniqKey="Flori E" first="E" last="Flori">E. Flori</name><affiliation><mods:affiliation>Service de Cytogénétique, Hôpital Hautepierre, CHU, Strasbourg, France</mods:affiliation></affiliation></author><author><name sortKey="Alex Ordier, Mp" sort="Alex Ordier, Mp" uniqKey="Alex Ordier M" first="Mp" last="Alex-Cordier">Mp Alex-Cordier</name><affiliation><mods:affiliation>Service de Génétique, Hospices Civils de Lyon, Bron, France</mods:affiliation></affiliation></author><author><name sortKey="Beri, M" sort="Beri, M" uniqKey="Beri M" first="M" last="Beri">M. Beri</name><affiliation><mods:affiliation>Laboratoire de Génétique Médicale, Hôpital Brabois, CHU, Nancy, France</mods:affiliation></affiliation></author><author><name sortKey="Boute, O" sort="Boute, O" uniqKey="Boute O" first="O" last="Boute">O. Boute</name><affiliation><mods:affiliation>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</mods:affiliation></affiliation></author><author><name sortKey="Delobel, B" sort="Delobel, B" uniqKey="Delobel B" first="B" last="Delobel">B. Delobel</name><affiliation><mods:affiliation>Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Dieux, A" sort="Dieux, A" uniqKey="Dieux A" first="A" last="Dieux">A. Dieux</name><affiliation><mods:affiliation>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</mods:affiliation></affiliation></author><author><name sortKey="Vallee, L" sort="Vallee, L" uniqKey="Vallee L" first="L" last="Vallee">L. Vallee</name><affiliation><mods:affiliation>Service de Neuropédiatrie, CHRU, Lille</mods:affiliation></affiliation></author><author><name sortKey="Jaillard, S" sort="Jaillard, S" uniqKey="Jaillard S" first="S" last="Jaillard">S. Jaillard</name><affiliation><mods:affiliation>Service de Cytogénétique, CHU, Rennes, France</mods:affiliation></affiliation></author><author><name sortKey="Odent, S" sort="Odent, S" uniqKey="Odent S" first="S" last="Odent">S. Odent</name><affiliation><mods:affiliation>Unité de Génétique Médicale, Hôpital Sud, CHU, Rennes, France</mods:affiliation></affiliation></author><author><name sortKey="Isidor, B" sort="Isidor, B" uniqKey="Isidor B" first="B" last="Isidor">B. Isidor</name><affiliation><mods:affiliation>Service de Génétique Médicale, CHU, Nantes</mods:affiliation></affiliation></author><author><name sortKey="Beneteau, C" sort="Beneteau, C" uniqKey="Beneteau C" first="C" last="Beneteau">C. Beneteau</name><affiliation><mods:affiliation>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France</mods:affiliation></affiliation></author><author><name sortKey="Vigneron, J" sort="Vigneron, J" uniqKey="Vigneron J" first="J" last="Vigneron">J. Vigneron</name><affiliation><mods:affiliation>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France</mods:affiliation></affiliation></author><author><name sortKey="Bilan, F" sort="Bilan, F" uniqKey="Bilan F" first="F" last="Bilan">F. Bilan</name><affiliation><mods:affiliation>Service de Génétique, CHU, Poitiers, France</mods:affiliation></affiliation></author><author><name sortKey="Gilbert Ussardier, B" sort="Gilbert Ussardier, B" uniqKey="Gilbert Ussardier B" first="B" last="Gilbert-Dussardier">B. Gilbert-Dussardier</name><affiliation><mods:affiliation>Service de Génétique, CHU, Poitiers, France</mods:affiliation></affiliation></author><author><name sortKey="Dubourg, C" sort="Dubourg, C" uniqKey="Dubourg C" first="C" last="Dubourg">C. Dubourg</name><affiliation><mods:affiliation>Laboratoire de Génétique Moléculaire, CHU, Rennes, France</mods:affiliation></affiliation></author><author><name sortKey="Labalme, A" sort="Labalme, A" uniqKey="Labalme A" first="A" last="Labalme">A. Labalme</name><affiliation><mods:affiliation>Service de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, GHE, Lyon, France</mods:affiliation></affiliation></author><author><name sortKey="Bidon, C" sort="Bidon, C" uniqKey="Bidon C" first="C" last="Bidon">C. Bidon</name><affiliation><mods:affiliation>Biologie Moléculaire, Plateau Technique de Biologie, CHU le Bocage, Dijon, France</mods:affiliation></affiliation></author><author><name sortKey="Gautier, A" sort="Gautier, A" uniqKey="Gautier A" first="A" last="Gautier">A. Gautier</name><affiliation><mods:affiliation>Neuropédiatrie, CHU, Nantes, France</mods:affiliation></affiliation></author><author><name sortKey="Pernes, P" sort="Pernes, P" uniqKey="Pernes P" first="P" last="Pernes">P. Pernes</name><affiliation><mods:affiliation>Centre de soins Saint Exupery, Vendin Le Vieil, France</mods:affiliation></affiliation></author><author><name sortKey="Pinoit, Jm" sort="Pinoit, Jm" uniqKey="Pinoit J" first="Jm" last="Pinoit">Jm Pinoit</name><affiliation><mods:affiliation>Service de Pédopsychiatrie</mods:affiliation></affiliation></author><author><name sortKey="Huet, F" sort="Huet, F" uniqKey="Huet F" first="F" last="Huet">F. Huet</name><affiliation><mods:affiliation>Service de Pédiatrie, Hôpital d’Enfants, CHU, Dijon, France</mods:affiliation></affiliation></author><author><name sortKey="Mugneret, F" sort="Mugneret, F" uniqKey="Mugneret F" first="F" last="Mugneret">F. Mugneret</name><affiliation><mods:affiliation>Service de cytogénétique, Plateau Technique de Biologie, CHU Le Bocage, Dijon</mods:affiliation></affiliation></author><author><name sortKey="Aral, B" sort="Aral, B" uniqKey="Aral B" first="B" last="Aral">B. Aral</name><affiliation><mods:affiliation>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France</mods:affiliation></affiliation></author><author><name sortKey="Jonveaux, P" sort="Jonveaux, P" uniqKey="Jonveaux P" first="P" last="Jonveaux">P. Jonveaux</name><affiliation><mods:affiliation>Laboratoire de Génétique Médicale, Hôpital Brabois, CHU, Nancy, France</mods:affiliation></affiliation></author><author><name sortKey="Sanlaville, D" sort="Sanlaville, D" uniqKey="Sanlaville D" first="D" last="Sanlaville">D. Sanlaville</name><affiliation><mods:affiliation>Service de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, GHE, Lyon, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Biologie Moléculaire, Plateau Technique de Biologie, CHU le Bocage, Dijon, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Neuropédiatrie, CHU, Nantes, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Centre de soins Saint Exupery, Vendin Le Vieil, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Service de Pédopsychiatrie</mods:affiliation></affiliation><affiliation><mods:affiliation>Service de Pédiatrie, Hôpital d’Enfants, CHU, Dijon, France</mods:affiliation></affiliation><affiliation><mods:affiliation>EA 4171, Université Claude Bernard Lyon 1, Lyon, France</mods:affiliation></affiliation></author><author><name sortKey="Faivre, L" sort="Faivre, L" uniqKey="Faivre L" first="L" last="Faivre">L. Faivre</name><affiliation><mods:affiliation>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: laurence.faivre@chu‐dijon.fr</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Clinical Genetics</title><title level="j" type="alt">CLINICAL GENETICS</title><idno type="ISSN">0009-9163</idno><idno type="eISSN">1399-0004</idno><imprint><biblScope unit="vol">78</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="149">149</biblScope><biblScope unit="page" to="161">161</biblScope><biblScope unit="page-count">13</biblScope><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2010-08">2010-08</date></imprint><idno type="ISSN">0009-9163</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0009-9163</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Masurel‐Paulet A, Andrieux J, Callier P, Cuisset JM, Le Caignec C, Holder M, Thauvin‐Robinet C, Doray B, Flori E, Alex‐Cordier MP, Beri M, Boute O, Delobel B, Dieux A, Vallee L, Jaillard S, Odent S, Isidor B, Beneteau C, Vigneron J, Bilan F, Gilbert‐Dussardier B, Dubourg C, Labalme A, Gautier A, Pernes P, Bidon C, Pinoit JM, Huet F, Mugneret F, Aral B, Jonveaux P, Sanlaville D, Faivre L. Delineation of 15q13.3 microdeletions. The increasing use of array‐comparative genomic hybridization (array‐CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the CHRNA7 gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4–BP5 microdeletion out of a series of 4625 patients screened by array‐CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of CHRNA7 yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical ∼1.5 Mb BP4–BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the CHRNA7 gene.</div></front></TEI><istex><corpusName>wiley</corpusName><keywords><teeft><json:string>microdeletion</json:string><json:string>chrna7</json:string><json:string>deletion</json:string><json:string>phenotype</json:string><json:string>genet</json:string><json:string>epilepsy</json:string><json:string>schizophrenia</json:string><json:string>mental retardation</json:string><json:string>microdeletions</json:string><json:string>dysmorphic</json:string><json:string>genetique</json:string><json:string>genomic</json:string><json:string>penetrance</json:string><json:string>cohort</json:string><json:string>dysmorphic features</json:string><json:string>genome</json:string><json:string>hopital</json:string><json:string>index 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genome</json:string></teeft></keywords><author><json:item><name>A Masurel‐Paulet</name><affiliations><json:string>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon</json:string></affiliations></json:item><json:item><name>J Andrieux</name><affiliations><json:string>Laboratoire de Génétique Médicale, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</json:string></affiliations></json:item><json:item><name>P Callier</name><affiliations><json:string>Service de cytogénétique, Plateau Technique de Biologie, CHU Le Bocage, Dijon</json:string></affiliations></json:item><json:item><name>JM Cuisset</name><affiliations><json:string>Service de Neuropédiatrie, CHRU, Lille</json:string></affiliations></json:item><json:item><name>C Le Caignec</name><affiliations><json:string>Service de Génétique Médicale, CHU, Nantes</json:string></affiliations></json:item><json:item><name>M Holder</name><affiliations><json:string>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</json:string></affiliations></json:item><json:item><name>C Thauvin‐Robinet</name><affiliations><json:string>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon</json:string></affiliations></json:item><json:item><name>B Doray</name><affiliations><json:string>Service de Génétique Médicale</json:string></affiliations></json:item><json:item><name>E Flori</name><affiliations><json:string>Service de Cytogénétique, Hôpital Hautepierre, CHU, Strasbourg, France</json:string></affiliations></json:item><json:item><name>MP Alex‐Cordier</name><affiliations><json:string>Service de Génétique, Hospices Civils de Lyon, Bron, France</json:string></affiliations></json:item><json:item><name>M Beri</name><affiliations><json:string>Laboratoire de Génétique Médicale, Hôpital Brabois, CHU, Nancy, France</json:string></affiliations></json:item><json:item><name>O Boute</name><affiliations><json:string>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</json:string></affiliations></json:item><json:item><name>B Delobel</name><affiliations><json:string>Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul, Lille, France</json:string></affiliations></json:item><json:item><name>A Dieux</name><affiliations><json:string>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</json:string></affiliations></json:item><json:item><name>L Vallee</name><affiliations><json:string>Service de Neuropédiatrie, CHRU, Lille</json:string></affiliations></json:item><json:item><name>S Jaillard</name><affiliations><json:string>Service de Cytogénétique, CHU, Rennes, France</json:string></affiliations></json:item><json:item><name>S Odent</name><affiliations><json:string>Unité de Génétique Médicale, Hôpital Sud, CHU, Rennes, France</json:string></affiliations></json:item><json:item><name>B Isidor</name><affiliations><json:string>Service de Génétique Médicale, CHU, Nantes</json:string></affiliations></json:item><json:item><name>C Beneteau</name><affiliations><json:string>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France</json:string></affiliations></json:item><json:item><name>J Vigneron</name><affiliations><json:string>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France</json:string></affiliations></json:item><json:item><name>F Bilan</name><affiliations><json:string>Service de Génétique, CHU, Poitiers, France</json:string></affiliations></json:item><json:item><name>B Gilbert‐Dussardier</name><affiliations><json:string>Service de Génétique, CHU, Poitiers, France</json:string></affiliations></json:item><json:item><name>C Dubourg</name><affiliations><json:string>Laboratoire de Génétique Moléculaire, CHU, Rennes, France</json:string></affiliations></json:item><json:item><name>A Labalme</name><affiliations><json:string>Service de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, GHE, Lyon, France</json:string></affiliations></json:item><json:item><name>C Bidon</name><affiliations><json:string>Biologie Moléculaire, Plateau Technique de Biologie, CHU le Bocage, Dijon, France</json:string></affiliations></json:item><json:item><name>A Gautier</name><affiliations><json:string>Neuropédiatrie, CHU, Nantes, France</json:string></affiliations></json:item><json:item><name>P Pernes</name><affiliations><json:string>Centre de soins Saint Exupery, Vendin Le Vieil, France</json:string></affiliations></json:item><json:item><name>JM Pinoit</name><affiliations><json:string>Service de Pédopsychiatrie</json:string></affiliations></json:item><json:item><name>F Huet</name><affiliations><json:string>Service de Pédiatrie, Hôpital d’Enfants, CHU, Dijon, France</json:string></affiliations></json:item><json:item><name>F Mugneret</name><affiliations><json:string>Service de cytogénétique, Plateau Technique de Biologie, CHU Le Bocage, Dijon</json:string></affiliations></json:item><json:item><name>B Aral</name><affiliations><json:string>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France</json:string></affiliations></json:item><json:item><name>P Jonveaux</name><affiliations><json:string>Laboratoire de Génétique Médicale, Hôpital Brabois, CHU, Nancy, France</json:string></affiliations></json:item><json:item><name>D Sanlaville</name><affiliations><json:string>Service de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, GHE, Lyon, France</json:string><json:string>Biologie Moléculaire, Plateau Technique de Biologie, CHU le Bocage, Dijon, France</json:string><json:string>Neuropédiatrie, CHU, Nantes, France</json:string><json:string>Centre de soins Saint Exupery, Vendin Le Vieil, France</json:string><json:string>Service de Pédopsychiatrie</json:string><json:string>Service de Pédiatrie, Hôpital d’Enfants, CHU, Dijon, France</json:string><json:string>EA 4171, Université Claude Bernard Lyon 1, Lyon, France</json:string></affiliations></json:item><json:item><name>L Faivre</name><affiliations><json:string>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon</json:string><json:string>E-mail: laurence.faivre@chu‐dijon.fr</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>15q13.3 microdeletion</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CHRNA7</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>homozygous deletion</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>incomplete penetrance</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>variable expressivity</value></json:item></subject><articleId><json:string>CGE1374</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>Masurel‐Paulet A, Andrieux J, Callier P, Cuisset JM, Le Caignec C, Holder M, Thauvin‐Robinet C, Doray B, Flori E, Alex‐Cordier MP, Beri M, Boute O, Delobel B, Dieux A, Vallee L, Jaillard S, Odent S, Isidor B, Beneteau C, Vigneron J, Bilan F, Gilbert‐Dussardier B, Dubourg C, Labalme A, Gautier A, Pernes P, Bidon C, Pinoit JM, Huet F, Mugneret F, Aral B, Jonveaux P, Sanlaville D, Faivre L. Delineation of 15q13.3 microdeletions. The increasing use of array‐comparative genomic hybridization (array‐CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the CHRNA7 gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4–BP5 microdeletion out of a series of 4625 patients screened by array‐CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of CHRNA7 yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical ∼1.5 Mb BP4–BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the CHRNA7 gene.</abstract><qualityIndicators><score>8</score><pdfVersion>1.3</pdfVersion><pdfPageSize>595.276 x 782.362 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>2192</abstractCharCount><pdfWordCount>5232</pdfWordCount><pdfCharCount>36962</pdfCharCount><pdfPageCount>13</pdfPageCount><abstractWordCount>324</abstractWordCount></qualityIndicators><title>Delineation of 15q13.3 microdeletions</title><genre><json:string>article</json:string></genre><host><title>Clinical Genetics</title><language><json:string>unknown</json:string></language><doi><json:string>10.1111/(ISSN)1399-0004</json:string></doi><issn><json:string>0009-9163</json:string></issn><eissn><json:string>1399-0004</json:string></eissn><publisherId><json:string>CGE</json:string></publisherId><volume>78</volume><issue>2</issue><pages><first>149</first><last>161</last><total>13</total></pages><genre><json:string>journal</json:string></genre></host><categories><wos><json:string>science</json:string><json:string>genetics & heredity</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>biomedical research</json:string><json:string>genetics & heredity</json:string></scienceMetrix><inist><json:string>sciences appliquees, technologies et medecines</json:string><json:string>sciences biologiques et medicales</json:string><json:string>sciences medicales</json:string><json:string>genetique 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UK</pubPlace><availability><licence>© 2010 John Wiley & Sons A/S</licence></availability><date type="published" when="2010-08"></date></publicationStmt><notesStmt><note type="content-type" subtype="article" source="article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</note><note type="publication-type" subtype="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="article"><analytic><title level="a" type="main">Delineation of 15q13.3 microdeletions</title><author xml:id="author-0000"><persName><forename type="first">A</forename><surname>Masurel‐Paulet</surname></persName><affiliation>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon<address><country key="ML"></country></address></affiliation><note type="foot">These authors contributed equally.</note></author><author xml:id="author-0001"><persName><forename type="first">J</forename><surname>Andrieux</surname></persName><affiliation>Laboratoire de Génétique Médicale, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</affiliation><note type="foot">These authors contributed equally.</note></author><author xml:id="author-0002"><persName><forename type="first">P</forename><surname>Callier</surname></persName><affiliation>Service de cytogénétique, Plateau Technique de Biologie, CHU Le Bocage, Dijon</affiliation></author><author xml:id="author-0003"><persName><forename type="first">JM</forename><surname>Cuisset</surname></persName><affiliation>Service de Neuropédiatrie, CHRU, Lille</affiliation></author><author xml:id="author-0004"><persName><forename type="first">C</forename><surname>Le Caignec</surname></persName><affiliation>Service de Génétique Médicale, CHU, Nantes</affiliation></author><author xml:id="author-0005"><persName><forename type="first">M</forename><surname>Holder</surname></persName><affiliation>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</affiliation></author><author xml:id="author-0006"><persName><forename type="first">C</forename><surname>Thauvin‐Robinet</surname></persName><affiliation>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon<address><country key="ML"></country></address></affiliation></author><author xml:id="author-0007"><persName><forename type="first">B</forename><surname>Doray</surname></persName><affiliation>Service de Génétique Médicale</affiliation></author><author xml:id="author-0008"><persName><forename type="first">E</forename><surname>Flori</surname></persName><affiliation>Service de Cytogénétique, Hôpital Hautepierre, CHU, Strasbourg, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0009"><persName><forename type="first">MP</forename><surname>Alex‐Cordier</surname></persName><affiliation>Service de Génétique, Hospices Civils de Lyon, Bron, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0010"><persName><forename type="first">M</forename><surname>Beri</surname></persName><affiliation>Laboratoire de Génétique Médicale, Hôpital Brabois, CHU, Nancy, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0011"><persName><forename type="first">O</forename><surname>Boute</surname></persName><affiliation>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</affiliation></author><author xml:id="author-0012"><persName><forename type="first">B</forename><surname>Delobel</surname></persName><affiliation>Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul, Lille, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0013"><persName><forename type="first">A</forename><surname>Dieux</surname></persName><affiliation>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</affiliation></author><author xml:id="author-0014"><persName><forename type="first">L</forename><surname>Vallee</surname></persName><affiliation>Service de Neuropédiatrie, CHRU, Lille</affiliation></author><author xml:id="author-0015"><persName><forename type="first">S</forename><surname>Jaillard</surname></persName><affiliation>Service de Cytogénétique, CHU, Rennes, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0016"><persName><forename type="first">S</forename><surname>Odent</surname></persName><affiliation>Unité de Génétique Médicale, Hôpital Sud, CHU, Rennes, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0017"><persName><forename type="first">B</forename><surname>Isidor</surname></persName><affiliation>Service de Génétique Médicale, CHU, Nantes</affiliation></author><author xml:id="author-0018"><persName><forename type="first">C</forename><surname>Beneteau</surname></persName><affiliation>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0019"><persName><forename type="first">J</forename><surname>Vigneron</surname></persName><affiliation>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0020"><persName><forename type="first">F</forename><surname>Bilan</surname></persName><affiliation>Service de Génétique, CHU, Poitiers, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0021"><persName><forename type="first">B</forename><surname>Gilbert‐Dussardier</surname></persName><affiliation>Service de Génétique, CHU, Poitiers, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0022"><persName><forename type="first">C</forename><surname>Dubourg</surname></persName><affiliation>Laboratoire de Génétique Moléculaire, CHU, Rennes, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0023"><persName><forename type="first">A</forename><surname>Labalme</surname></persName><affiliation>Service de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, GHE, Lyon, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0024"><persName><forename type="first">C</forename><surname>Bidon</surname></persName><affiliation>Biologie Moléculaire, Plateau Technique de Biologie, CHU le Bocage, Dijon, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0025"><persName><forename type="first">A</forename><surname>Gautier</surname></persName><affiliation>Neuropédiatrie, CHU, Nantes, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0026"><persName><forename type="first">P</forename><surname>Pernes</surname></persName><affiliation>Centre de soins Saint Exupery, Vendin Le Vieil, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0027"><persName><forename type="first">JM</forename><surname>Pinoit</surname></persName><affiliation>Service de Pédopsychiatrie</affiliation></author><author xml:id="author-0028"><persName><forename type="first">F</forename><surname>Huet</surname></persName><affiliation>Service de Pédiatrie, Hôpital d’Enfants, CHU, Dijon, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0029"><persName><forename type="first">F</forename><surname>Mugneret</surname></persName><affiliation>Service de cytogénétique, Plateau Technique de Biologie, CHU Le Bocage, Dijon</affiliation></author><author xml:id="author-0030"><persName><forename type="first">B</forename><surname>Aral</surname></persName><affiliation>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0031"><persName><forename type="first">P</forename><surname>Jonveaux</surname></persName><affiliation>Laboratoire de Génétique Médicale, Hôpital Brabois, CHU, Nancy, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0032"><persName><forename type="first">D</forename><surname>Sanlaville</surname></persName><affiliation>Service de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, GHE, Lyon, France<address><country key="FR"></country></address></affiliation><affiliation>Biologie Moléculaire, Plateau Technique de Biologie, CHU le Bocage, Dijon, France<address><country key="FR"></country></address></affiliation><affiliation>Neuropédiatrie, CHU, Nantes, France<address><country key="FR"></country></address></affiliation><affiliation>Centre de soins Saint Exupery, Vendin Le Vieil, France<address><country key="FR"></country></address></affiliation><affiliation>Service de Pédopsychiatrie</affiliation><affiliation>Service de Pédiatrie, Hôpital d’Enfants, CHU, Dijon, France<address><country key="FR"></country></address></affiliation><affiliation>EA 4171, Université Claude Bernard Lyon 1, Lyon, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0033" role="corresp"><persName><forename type="first">L</forename><surname>Faivre</surname></persName><affiliation>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon<address><country key="ML"></country></address></affiliation><affiliation>Laurence Faivre, MD, PhD, Centre de Génétique, Hôpital d’Enfants, 10 bd Maréchal de Lattre de Tassigny, 21034 Dijon Cedex, France.
Tel.: +33 380 295 313;
fax: +33 380 293 266;
e‐mail: laurence.faivre@chu‐dijon.fr</affiliation></author><idno type="istex">B66C60804B18AC075AB8BC4FD727A1408605E2AD</idno><idno type="DOI">10.1111/j.1399-0004.2010.01374.x</idno><idno type="unit">CGE1374</idno><idno type="toTypesetVersion">file:CGE.CGE1374.pdf</idno></analytic><monogr><title level="j" type="main">Clinical Genetics</title><title level="j" type="alt">CLINICAL GENETICS</title><idno type="pISSN">0009-9163</idno><idno type="eISSN">1399-0004</idno><idno type="book-DOI">10.1111/(ISSN)1399-0004</idno><idno type="book-part-DOI">10.1111/cge.2010.78.issue-2</idno><idno type="product">CGE</idno><idno type="publisherDivision">ST</idno><imprint><biblScope unit="vol">78</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="149">149</biblScope><biblScope unit="page" to="161">161</biblScope><biblScope unit="page-count">13</biblScope><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2010-08"></date></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><abstract xml:lang="en" style="main"><p>Masurel‐Paulet A, Andrieux J, Callier P, Cuisset JM, Le Caignec C, Holder M, Thauvin‐Robinet C, Doray B, Flori E, Alex‐Cordier MP, Beri M, Boute O, Delobel B, Dieux A, Vallee L, Jaillard S, Odent S, Isidor B, Beneteau C, Vigneron J, Bilan F, Gilbert‐Dussardier B, Dubourg C, Labalme A, Gautier A, Pernes P, Bidon C, Pinoit JM, Huet F, Mugneret F, Aral B, Jonveaux P, Sanlaville D, Faivre L. Delineation of 15q13.3 microdeletions.</p><p>The increasing use of array‐comparative genomic hybridization (array‐CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the <hi rend="italic">CHRNA7</hi> gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4–BP5 microdeletion out of a series of 4625 patients screened by array‐CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of <hi rend="italic">CHRNA7</hi> yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical ∼1.5 Mb BP4–BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the <hi rend="italic">CHRNA7</hi> gene.</p></abstract><textClass><keywords xml:lang="en"><term xml:id="k1">15q13.3 microdeletion</term><term xml:id="k2"><hi rend="italic">CHRNA7</hi></term><term xml:id="k3">homozygous deletion</term><term xml:id="k4">incomplete penetrance</term><term xml:id="k5">variable expressivity</term></keywords><classCode scheme="tocHeading1">Short Reports</classCode></textClass><langUsage><language ident="EN"></language></langUsage></profileDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/B66C60804B18AC075AB8BC4FD727A1408605E2AD/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Blackwell Publishing Ltd</publisherName><publisherLoc>Oxford, UK</publisherLoc></publisherInfo><doi origin="wiley" registered="yes">10.1111/(ISSN)1399-0004</doi><issn type="print">0009-9163</issn><issn type="electronic">1399-0004</issn><idGroup><id type="product" value="CGE"></id><id type="publisherDivision" value="ST"></id></idGroup><titleGroup><title type="main" sort="CLINICAL GENETICS">Clinical Genetics</title></titleGroup></publicationMeta><publicationMeta level="part" position="08002"><doi origin="wiley">10.1111/cge.2010.78.issue-2</doi><numberingGroup><numbering type="journalVolume" number="78">78</numbering><numbering type="journalIssue" number="2">2</numbering></numberingGroup><coverDate startDate="2010-08">August 2010</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="7" status="forIssue"><doi origin="wiley">10.1111/j.1399-0004.2010.01374.x</doi><idGroup><id type="unit" value="CGE1374"></id></idGroup><countGroup><count type="pageTotal" number="13"></count></countGroup><titleGroup><title type="tocHeading1">Short Reports</title></titleGroup><copyright>© 2010 John Wiley & Sons A/S</copyright><eventGroup><event type="firstOnline" date="2010-02-09"></event><event type="publishedOnlineFinalForm" date="2010-07-06"></event><event type="xmlConverted" agent="Converter:BPG_TO_WML3G version:2.3.15 mode:FullText source:HeaderRef result:HeaderRef" date="2010-07-21"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-09"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-16"></event></eventGroup><numberingGroup><numbering type="pageFirst" number="149">149</numbering><numbering type="pageLast" number="161">161</numbering></numberingGroup><correspondenceTo>Laurence Faivre, MD, PhD, Centre de Génétique, Hôpital d’Enfants, 10 bd Maréchal de Lattre de Tassigny, 21034 Dijon Cedex, France.
Tel.: +33 380 295 313;
fax: +33 380 293 266;
e‐mail: <email normalForm="laurence.faivre@chu-dijon.fr">laurence.faivre@chu‐dijon.fr</email></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:CGE.CGE1374.pdf"></link></linkGroup></publicationMeta><contentMeta><unparsedEditorialHistory>Received 8 September 2009, revised and accepted for publication 4 January 2010</unparsedEditorialHistory><countGroup><count type="figureTotal" number="3"></count><count type="tableTotal" number="2"></count><count type="formulaTotal" number="0"></count><count type="referenceTotal" number="28"></count></countGroup><titleGroup><title type="main">Delineation of 15q13.3 microdeletions</title><title type="shortAuthors">Masurel‐Paulet et al.</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1" noteRef="#fn1"><personName><givenNames>A</givenNames><familyName>Masurel‐Paulet</familyName></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a2" 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affiliationRef="#a10"><personName><givenNames>P</givenNames><familyName>Jonveaux</familyName></personName></creator><creator creatorRole="author" xml:id="cr33" affiliationRef="#a17 #a18 #a19 #a20 #a21 #a22 #a23"><personName><givenNames>D</givenNames><familyName>Sanlaville</familyName></personName></creator><creator creatorRole="author" xml:id="cr34" affiliationRef="#a1" corresponding="yes"><personName><givenNames>L</givenNames><familyName>Faivre</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="ML"><unparsedAffiliation>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon</unparsedAffiliation></affiliation><affiliation xml:id="a2"><unparsedAffiliation>Laboratoire de Génétique Médicale, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</unparsedAffiliation></affiliation><affiliation xml:id="a3"><unparsedAffiliation>Service de cytogénétique, Plateau Technique de Biologie, CHU 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CHU, Nancy, France</unparsedAffiliation></affiliation><affiliation xml:id="a11" countryCode="FR"><unparsedAffiliation>Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul, Lille, France</unparsedAffiliation></affiliation><affiliation xml:id="a12" countryCode="FR"><unparsedAffiliation>Service de Cytogénétique, CHU, Rennes, France</unparsedAffiliation></affiliation><affiliation xml:id="a13" countryCode="FR"><unparsedAffiliation>Unité de Génétique Médicale, Hôpital Sud, CHU, Rennes, France</unparsedAffiliation></affiliation><affiliation xml:id="a14" countryCode="FR"><unparsedAffiliation>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France</unparsedAffiliation></affiliation><affiliation xml:id="a15" countryCode="FR"><unparsedAffiliation>Service de Génétique, CHU, Poitiers, France</unparsedAffiliation></affiliation><affiliation xml:id="a16" countryCode="FR"><unparsedAffiliation>Laboratoire de Génétique Moléculaire, CHU, Rennes, France</unparsedAffiliation></affiliation><affiliation xml:id="a17" countryCode="FR"><unparsedAffiliation>Service de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, GHE, Lyon, France</unparsedAffiliation></affiliation><affiliation xml:id="a18" countryCode="FR"><unparsedAffiliation>Biologie Moléculaire, Plateau Technique de Biologie, CHU le Bocage, Dijon, France</unparsedAffiliation></affiliation><affiliation xml:id="a19" countryCode="FR"><unparsedAffiliation>Neuropédiatrie, CHU, Nantes, France</unparsedAffiliation></affiliation><affiliation xml:id="a20" countryCode="FR"><unparsedAffiliation>Centre de soins Saint Exupery, Vendin Le Vieil, France</unparsedAffiliation></affiliation><affiliation xml:id="a21"><unparsedAffiliation>Service de Pédopsychiatrie</unparsedAffiliation></affiliation><affiliation xml:id="a22" countryCode="FR"><unparsedAffiliation>Service de Pédiatrie, Hôpital d’Enfants, CHU, Dijon, France</unparsedAffiliation></affiliation><affiliation xml:id="a23" countryCode="FR"><unparsedAffiliation>EA 4171, Université Claude Bernard Lyon 1, Lyon, France</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en"><keyword xml:id="k1">15q13.3 microdeletion</keyword><keyword xml:id="k2"><i>CHRNA7</i></keyword><keyword xml:id="k3">homozygous deletion</keyword><keyword xml:id="k4">incomplete penetrance</keyword><keyword xml:id="k5">variable expressivity</keyword></keywordGroup><supportingInformation><p><b>Supporting Information</b></p><p>The following supporting information is available for this article:</p><p>Fig. S1. Photographs of eight patients with a ∼1.5 Mb
BP4–BP5 15q13.3 microdeletion. (A) Index case family 1; (B)
index case family 5; (C) index case family 6; (D) index case family
7; (E) affected mother's family 7; (F) index case family
9; (G) index case family 10; (H) affected sister's family
10; (I) index case family 8.</p><p>Fig. S2. Pedigrees of families 1–12 carrying a
heterozygous ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. In
family 7, the index patient had a sibling who died in the first
month of life in a context of multiple congenital abnormalities
including vertebral malformations, complex heart malformation, lung
hypoplasia, imperforate anus, camptodactyly and facial dysmorphism,
but no sample was available for this relative. In family 12, the
mother had a 47,XXX karyotype.
Developmental delay (DD); seizures;
patient carrying the 15q13.3
microdeletion; abnormal behaviour,
including anxiety, inhibition or hyperactivity (see Table 1 for
probands); autism; patient negative for the 15q13.3 microdeletion.</p><p>Additional Supporting Information may be found in the online version of this article.</p><p>Table S1: Characteristics of microarrays used for the analyses, results and methods for confirmation.</p><p>Table S2: Variants identified within the <i>CHRNA7</i> gene in 9 index patients reported in the study.</p><supportingInfoItem><mediaResource alt="supporting info item" href="urn-x:wiley:00099163:media:cge1374:CGE_1374_sm_tableS1"></mediaResource><caption>Supporting info item</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting info item" href="urn-x:wiley:00099163:media:cge1374:CGE_1374_sm_tableS2"></mediaResource><caption>Supporting info item</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting info item" href="urn-x:wiley:00099163:media:cge1374:CGE_1374_sm_figS1"></mediaResource><caption>Supporting info item</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting info item" href="urn-x:wiley:00099163:media:cge1374:CGE_1374_sm_figS2"></mediaResource><caption>Supporting info item</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><p>Masurel‐Paulet A, Andrieux J, Callier P, Cuisset JM, Le Caignec C, Holder M, Thauvin‐Robinet C, Doray B, Flori E, Alex‐Cordier MP, Beri M, Boute O, Delobel B, Dieux A, Vallee L, Jaillard S, Odent S, Isidor B, Beneteau C, Vigneron J, Bilan F, Gilbert‐Dussardier B, Dubourg C, Labalme A, Gautier A, Pernes P, Bidon C, Pinoit JM, Huet F, Mugneret F, Aral B, Jonveaux P, Sanlaville D, Faivre L. Delineation of 15q13.3 microdeletions.</p><p>The increasing use of array‐comparative genomic hybridization (array‐CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the <i>CHRNA7</i> gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4–BP5 microdeletion out of a series of 4625 patients screened by array‐CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of <i>CHRNA7</i> yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical ∼1.5 Mb BP4–BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the <i>CHRNA7</i> gene.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><label><sup>*</sup></label><p>These authors contributed equally.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Delineation of 15q13.3 microdeletions</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Delineation of 15q13.3 microdeletions</title></titleInfo><name type="personal"><namePart type="given">A</namePart><namePart type="family">Masurel‐Paulet</namePart><affiliation>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon</affiliation><description>These authors contributed equally.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">J</namePart><namePart type="family">Andrieux</namePart><affiliation>Laboratoire de Génétique Médicale, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</affiliation><description>These authors contributed equally.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">P</namePart><namePart type="family">Callier</namePart><affiliation>Service de cytogénétique, Plateau Technique de Biologie, CHU Le Bocage, Dijon</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">JM</namePart><namePart type="family">Cuisset</namePart><affiliation>Service de Neuropédiatrie, CHRU, Lille</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C</namePart><namePart type="family">Le Caignec</namePart><affiliation>Service de Génétique Médicale, CHU, Nantes</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Holder</namePart><affiliation>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C</namePart><namePart type="family">Thauvin‐Robinet</namePart><affiliation>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">B</namePart><namePart type="family">Doray</namePart><affiliation>Service de Génétique Médicale</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">E</namePart><namePart type="family">Flori</namePart><affiliation>Service de Cytogénétique, Hôpital Hautepierre, CHU, Strasbourg, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">MP</namePart><namePart type="family">Alex‐Cordier</namePart><affiliation>Service de Génétique, Hospices Civils de Lyon, Bron, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Beri</namePart><affiliation>Laboratoire de Génétique Médicale, Hôpital Brabois, CHU, Nancy, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">O</namePart><namePart type="family">Boute</namePart><affiliation>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">B</namePart><namePart type="family">Delobel</namePart><affiliation>Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul, Lille, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Dieux</namePart><affiliation>Service de Génétique Clinique, Hôpital Jeanne‐de‐Flandre, CHRU, Lille</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">L</namePart><namePart type="family">Vallee</namePart><affiliation>Service de Neuropédiatrie, CHRU, Lille</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Jaillard</namePart><affiliation>Service de Cytogénétique, CHU, Rennes, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Odent</namePart><affiliation>Unité de Génétique Médicale, Hôpital Sud, CHU, Rennes, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">B</namePart><namePart type="family">Isidor</namePart><affiliation>Service de Génétique Médicale, CHU, Nantes</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C</namePart><namePart type="family">Beneteau</namePart><affiliation>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">J</namePart><namePart type="family">Vigneron</namePart><affiliation>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">F</namePart><namePart type="family">Bilan</namePart><affiliation>Service de Génétique, CHU, Poitiers, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">B</namePart><namePart type="family">Gilbert‐Dussardier</namePart><affiliation>Service de Génétique, CHU, Poitiers, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C</namePart><namePart type="family">Dubourg</namePart><affiliation>Laboratoire de Génétique Moléculaire, CHU, Rennes, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Labalme</namePart><affiliation>Service de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, GHE, Lyon, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C</namePart><namePart type="family">Bidon</namePart><affiliation>Biologie Moléculaire, Plateau Technique de Biologie, CHU le Bocage, Dijon, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Gautier</namePart><affiliation>Neuropédiatrie, CHU, Nantes, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">P</namePart><namePart type="family">Pernes</namePart><affiliation>Centre de soins Saint Exupery, Vendin Le Vieil, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">JM</namePart><namePart type="family">Pinoit</namePart><affiliation>Service de Pédopsychiatrie</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">F</namePart><namePart type="family">Huet</namePart><affiliation>Service de Pédiatrie, Hôpital d’Enfants, CHU, Dijon, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">F</namePart><namePart type="family">Mugneret</namePart><affiliation>Service de cytogénétique, Plateau Technique de Biologie, CHU Le Bocage, Dijon</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">B</namePart><namePart type="family">Aral</namePart><affiliation>Service de Néonatologie‐Génétique, Maternité Régionale Universitaire, Nancy, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">P</namePart><namePart type="family">Jonveaux</namePart><affiliation>Laboratoire de Génétique Médicale, Hôpital Brabois, CHU, Nancy, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">D</namePart><namePart type="family">Sanlaville</namePart><affiliation>Service de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, GHE, Lyon, France</affiliation><affiliation>Biologie Moléculaire, Plateau Technique de Biologie, CHU le Bocage, Dijon, France</affiliation><affiliation>Neuropédiatrie, CHU, Nantes, France</affiliation><affiliation>Centre de soins Saint Exupery, Vendin Le Vieil, France</affiliation><affiliation>Service de Pédopsychiatrie</affiliation><affiliation>Service de Pédiatrie, Hôpital d’Enfants, CHU, Dijon, France</affiliation><affiliation>EA 4171, Université Claude Bernard Lyon 1, Lyon, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">L</namePart><namePart type="family">Faivre</namePart><affiliation>Centre de Génétique et Centre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d’Enfants, CHU, Dijon</affiliation><affiliation>E-mail: laurence.faivre@chu‐dijon.fr</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><place><placeTerm type="text">Oxford, UK</placeTerm></place><dateIssued encoding="w3cdtf">2010-08</dateIssued><edition>Received 8 September 2009, revised and accepted for publication 4 January 2010</edition><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">3</extent><extent unit="tables">2</extent><extent unit="references">28</extent></physicalDescription><abstract lang="en">Masurel‐Paulet A, Andrieux J, Callier P, Cuisset JM, Le Caignec C, Holder M, Thauvin‐Robinet C, Doray B, Flori E, Alex‐Cordier MP, Beri M, Boute O, Delobel B, Dieux A, Vallee L, Jaillard S, Odent S, Isidor B, Beneteau C, Vigneron J, Bilan F, Gilbert‐Dussardier B, Dubourg C, Labalme A, Gautier A, Pernes P, Bidon C, Pinoit JM, Huet F, Mugneret F, Aral B, Jonveaux P, Sanlaville D, Faivre L. Delineation of 15q13.3 microdeletions. The increasing use of array‐comparative genomic hybridization (array‐CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the CHRNA7 gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4–BP5 microdeletion out of a series of 4625 patients screened by array‐CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of CHRNA7 yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical ∼1.5 Mb BP4–BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the CHRNA7 gene.</abstract><subject lang="en"><genre>keywords</genre><topic>15q13.3 microdeletion</topic><topic>CHRNA7</topic><topic>homozygous deletion</topic><topic>incomplete penetrance</topic><topic>variable expressivity</topic></subject><relatedItem type="host"><titleInfo><title>Clinical Genetics</title></titleInfo><genre type="journal">journal</genre><note type="content"> Supporting Information The following supporting information is available for this article: Fig. S1. Photographs of eight patients with a ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. (A) Index case family 1; (B) index case family 5; (C) index case family 6; (D) index case family 7; (E) affected mother's family 7; (F) index case family 9; (G) index case family 10; (H) affected sister's family 10; (I) index case family 8. Fig. S2. Pedigrees of families 1–12 carrying a heterozygous ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. In family 7, the index patient had a sibling who died in the first month of life in a context of multiple congenital abnormalities including vertebral malformations, complex heart malformation, lung hypoplasia, imperforate anus, camptodactyly and facial dysmorphism, but no sample was available for this relative. In family 12, the mother had a 47,XXX karyotype. Developmental delay (DD); seizures; patient carrying the 15q13.3 microdeletion; abnormal behaviour, including anxiety, inhibition or hyperactivity (see Table 1 for probands); autism; patient negative for the 15q13.3 microdeletion. Additional Supporting Information may be found in the online version of this article. Table S1: Characteristics of microarrays used for the analyses, results and methods for confirmation. Table S2: Variants identified within the CHRNA7 gene in 9 index patients reported in the study. Supporting Information The following supporting information is available for this article: Fig. S1. Photographs of eight patients with a ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. (A) Index case family 1; (B) index case family 5; (C) index case family 6; (D) index case family 7; (E) affected mother's family 7; (F) index case family 9; (G) index case family 10; (H) affected sister's family 10; (I) index case family 8. Fig. S2. Pedigrees of families 1–12 carrying a heterozygous ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. In family 7, the index patient had a sibling who died in the first month of life in a context of multiple congenital abnormalities including vertebral malformations, complex heart malformation, lung hypoplasia, imperforate anus, camptodactyly and facial dysmorphism, but no sample was available for this relative. In family 12, the mother had a 47,XXX karyotype. Developmental delay (DD); seizures; patient carrying the 15q13.3 microdeletion; abnormal behaviour, including anxiety, inhibition or hyperactivity (see Table 1 for probands); autism; patient negative for the 15q13.3 microdeletion. Additional Supporting Information may be found in the online version of this article. Table S1: Characteristics of microarrays used for the analyses, results and methods for confirmation. Table S2: Variants identified within the CHRNA7 gene in 9 index patients reported in the study. Supporting Information The following supporting information is available for this article: Fig. S1. Photographs of eight patients with a ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. (A) Index case family 1; (B) index case family 5; (C) index case family 6; (D) index case family 7; (E) affected mother's family 7; (F) index case family 9; (G) index case family 10; (H) affected sister's family 10; (I) index case family 8. Fig. S2. Pedigrees of families 1–12 carrying a heterozygous ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. In family 7, the index patient had a sibling who died in the first month of life in a context of multiple congenital abnormalities including vertebral malformations, complex heart malformation, lung hypoplasia, imperforate anus, camptodactyly and facial dysmorphism, but no sample was available for this relative. In family 12, the mother had a 47,XXX karyotype. Developmental delay (DD); seizures; patient carrying the 15q13.3 microdeletion; abnormal behaviour, including anxiety, inhibition or hyperactivity (see Table 1 for probands); autism; patient negative for the 15q13.3 microdeletion. Additional Supporting Information may be found in the online version of this article. Table S1: Characteristics of microarrays used for the analyses, results and methods for confirmation. Table S2: Variants identified within the CHRNA7 gene in 9 index patients reported in the study. Supporting Information The following supporting information is available for this article: Fig. S1. Photographs of eight patients with a ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. (A) Index case family 1; (B) index case family 5; (C) index case family 6; (D) index case family 7; (E) affected mother's family 7; (F) index case family 9; (G) index case family 10; (H) affected sister's family 10; (I) index case family 8. Fig. S2. Pedigrees of families 1–12 carrying a heterozygous ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. In family 7, the index patient had a sibling who died in the first month of life in a context of multiple congenital abnormalities including vertebral malformations, complex heart malformation, lung hypoplasia, imperforate anus, camptodactyly and facial dysmorphism, but no sample was available for this relative. In family 12, the mother had a 47,XXX karyotype. Developmental delay (DD); seizures; patient carrying the 15q13.3 microdeletion; abnormal behaviour, including anxiety, inhibition or hyperactivity (see Table 1 for probands); autism; patient negative for the 15q13.3 microdeletion. Additional Supporting Information may be found in the online version of this article. Table S1: Characteristics of microarrays used for the analyses, results and methods for confirmation. Table S2: Variants identified within the CHRNA7 gene in 9 index patients reported in the study. Supporting Information The following supporting information is available for this article: Fig. S1. Photographs of eight patients with a ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. (A) Index case family 1; (B) index case family 5; (C) index case family 6; (D) index case family 7; (E) affected mother's family 7; (F) index case family 9; (G) index case family 10; (H) affected sister's family 10; (I) index case family 8. Fig. S2. Pedigrees of families 1–12 carrying a heterozygous ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. In family 7, the index patient had a sibling who died in the first month of life in a context of multiple congenital abnormalities including vertebral malformations, complex heart malformation, lung hypoplasia, imperforate anus, camptodactyly and facial dysmorphism, but no sample was available for this relative. In family 12, the mother had a 47,XXX karyotype. Developmental delay (DD); seizures; patient carrying the 15q13.3 microdeletion; abnormal behaviour, including anxiety, inhibition or hyperactivity (see Table 1 for probands); autism; patient negative for the 15q13.3 microdeletion. Additional Supporting Information may be found in the online version of this article. Table S1: Characteristics of microarrays used for the analyses, results and methods for confirmation. Table S2: Variants identified within the CHRNA7 gene in 9 index patients reported in the study. Supporting Information The following supporting information is available for this article: Fig. S1. Photographs of eight patients with a ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. (A) Index case family 1; (B) index case family 5; (C) index case family 6; (D) index case family 7; (E) affected mother's family 7; (F) index case family 9; (G) index case family 10; (H) affected sister's family 10; (I) index case family 8. Fig. S2. Pedigrees of families 1–12 carrying a heterozygous ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. In family 7, the index patient had a sibling who died in the first month of life in a context of multiple congenital abnormalities including vertebral malformations, complex heart malformation, lung hypoplasia, imperforate anus, camptodactyly and facial dysmorphism, but no sample was available for this relative. In family 12, the mother had a 47,XXX karyotype. Developmental delay (DD); seizures; patient carrying the 15q13.3 microdeletion; abnormal behaviour, including anxiety, inhibition or hyperactivity (see Table 1 for probands); autism; patient negative for the 15q13.3 microdeletion. Additional Supporting Information may be found in the online version of this article. Table S1: Characteristics of microarrays used for the analyses, results and methods for confirmation. Table S2: Variants identified within the CHRNA7 gene in 9 index patients reported in the study. Supporting Information The following supporting information is available for this article: Fig. S1. Photographs of eight patients with a ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. (A) Index case family 1; (B) index case family 5; (C) index case family 6; (D) index case family 7; (E) affected mother's family 7; (F) index case family 9; (G) index case family 10; (H) affected sister's family 10; (I) index case family 8. Fig. S2. Pedigrees of families 1–12 carrying a heterozygous ∼1.5 Mb BP4–BP5 15q13.3 microdeletion. In family 7, the index patient had a sibling who died in the first month of life in a context of multiple congenital abnormalities including vertebral malformations, complex heart malformation, lung hypoplasia, imperforate anus, camptodactyly and facial dysmorphism, but no sample was available for this relative. In family 12, the mother had a 47,XXX karyotype. Developmental delay (DD); seizures; patient carrying the 15q13.3 microdeletion; abnormal behaviour, including anxiety, inhibition or hyperactivity (see Table 1 for probands); autism; patient negative for the 15q13.3 microdeletion. Additional Supporting Information may be found in the online version of this article. Table S1: Characteristics of microarrays used for the analyses, results and methods for confirmation. Table S2: Variants identified within the CHRNA7 gene in 9 index patients reported in the study.Supporting Info Item: Supporting info item - Supporting info item - Supporting info item - Supporting info item - </note><identifier type="ISSN">0009-9163</identifier><identifier type="eISSN">1399-0004</identifier><identifier type="DOI">10.1111/(ISSN)1399-0004</identifier><identifier type="PublisherID">CGE</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>78</number></detail><detail type="issue"><caption>no.</caption><number>2</number></detail><extent unit="pages"><start>149</start><end>161</end><total>13</total></extent></part></relatedItem><identifier type="istex">B66C60804B18AC075AB8BC4FD727A1408605E2AD</identifier><identifier type="DOI">10.1111/j.1399-0004.2010.01374.x</identifier><identifier type="ArticleID">CGE1374</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2010 John Wiley & Sons A/S</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Blackwell Publishing Ltd</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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