Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies.
Identifieur interne : 000F89 ( PubMed/Corpus ); précédent : 000F88; suivant : 000F90Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies.
Auteurs : Rocio Acuna-Hidalgo ; Pelagia Deriziotis ; Marloes Steehouwer ; Christian Gilissen ; Sarah A. Graham ; Sipko Van Dam ; Julie Hoover-Fong ; Aida B. Telegrafi ; Anne Destree ; Robert Smigiel ; Lindsday A. Lambie ; Hülya Kayserili ; Umut Altunoglu ; Elisabetta Lapi ; Maria Luisa Uzielli ; Mariana Aracena ; Banu G. Nur ; Ercan Mihci ; Lilia M A. Moreira ; Viviane Borges Ferreira ; Dafne D G. Horovitz ; Katia M. Da Rocha ; Aleksandra Jezela-Stanek ; Alice S. Brooks ; Heiko Reutter ; Julie S. Cohen ; Ali Fatemi ; Martin Smitka ; Theresa A. Grebe ; Nataliya Di Donato ; Charu Deshpande ; Anthony Vandersteen ; Charles Marques Lourenço ; Andreas Dufke ; Eva Rossier ; Gwenaelle Andre ; Alessandra Baumer ; Careni Spencer ; Julie Mcgaughran ; Lude Franke ; Joris A. Veltman ; Bert B A. De Vries ; Albert Schinzel ; Simon E. Fisher ; Alexander Hoischen ; Bregje W. Van BonSource :
- PLoS genetics [ 1553-7404 ] ; 2017.
English descriptors
- KwdEn :
- Abnormalities, Multiple (genetics), Abnormalities, Multiple (metabolism), Abnormalities, Multiple (pathology), Blotting, Western, Carrier Proteins (genetics), Carrier Proteins (metabolism), Cell Line, Cell Proliferation (genetics), Cell Transformation, Neoplastic (genetics), Child, Child, Preschool, Craniofacial Abnormalities (genetics), Craniofacial Abnormalities (metabolism), Craniofacial Abnormalities (pathology), Female, Gene Expression Profiling, Genetic Association Studies, Genetic Predisposition to Disease (genetics), Germ-Line Mutation, HEK293 Cells, Hand Deformities, Congenital (genetics), Hand Deformities, Congenital (metabolism), Hand Deformities, Congenital (pathology), Hematologic Neoplasms (genetics), Hematologic Neoplasms (metabolism), Hematologic Neoplasms (pathology), Humans, Infant, Infant, Newborn, Intellectual Disability (genetics), Intellectual Disability (metabolism), Intellectual Disability (pathology), Male, Mutation, Nails, Malformed (genetics), Nails, Malformed (metabolism), Nails, Malformed (pathology), Nuclear Proteins (genetics), Nuclear Proteins (metabolism), Phenotype.
- MESH :
- chemical , genetics : Carrier Proteins, Nuclear Proteins.
- genetics : Abnormalities, Multiple, Cell Proliferation, Cell Transformation, Neoplastic, Craniofacial Abnormalities, Genetic Predisposition to Disease, Hand Deformities, Congenital, Hematologic Neoplasms, Intellectual Disability, Nails, Malformed.
- metabolism : Abnormalities, Multiple, Carrier Proteins, Craniofacial Abnormalities, Hand Deformities, Congenital, Hematologic Neoplasms, Intellectual Disability, Nails, Malformed, Nuclear Proteins.
- pathology : Abnormalities, Multiple, Craniofacial Abnormalities, Hand Deformities, Congenital, Hematologic Neoplasms, Intellectual Disability, Nails, Malformed.
- Blotting, Western, Cell Line, Child, Child, Preschool, Female, Gene Expression Profiling, Genetic Association Studies, Germ-Line Mutation, HEK293 Cells, Humans, Infant, Infant, Newborn, Male, Mutation, Phenotype.
Abstract
Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.
DOI: 10.1371/journal.pgen.1006683
PubMed: 28346496
Links to Exploration step
pubmed:28346496Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies.</title><author><name sortKey="Acuna Hidalgo, Rocio" sort="Acuna Hidalgo, Rocio" uniqKey="Acuna Hidalgo R" first="Rocio" last="Acuna-Hidalgo">Rocio Acuna-Hidalgo</name><affiliation><nlm:affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Deriziotis, Pelagia" sort="Deriziotis, Pelagia" uniqKey="Deriziotis P" first="Pelagia" last="Deriziotis">Pelagia Deriziotis</name><affiliation><nlm:affiliation>Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Steehouwer, Marloes" sort="Steehouwer, Marloes" uniqKey="Steehouwer M" first="Marloes" last="Steehouwer">Marloes Steehouwer</name><affiliation><nlm:affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Gilissen, Christian" sort="Gilissen, Christian" uniqKey="Gilissen C" first="Christian" last="Gilissen">Christian Gilissen</name><affiliation><nlm:affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Graham, Sarah A" sort="Graham, Sarah A" uniqKey="Graham S" first="Sarah A" last="Graham">Sarah A. Graham</name><affiliation><nlm:affiliation>Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Van Dam, Sipko" sort="Van Dam, Sipko" uniqKey="Van Dam S" first="Sipko" last="Van Dam">Sipko Van Dam</name><affiliation><nlm:affiliation>University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Hoover Fong, Julie" sort="Hoover Fong, Julie" uniqKey="Hoover Fong J" first="Julie" last="Hoover-Fong">Julie Hoover-Fong</name><affiliation><nlm:affiliation>McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.</nlm:affiliation></affiliation></author><author><name sortKey="Telegrafi, Aida B" sort="Telegrafi, Aida B" uniqKey="Telegrafi A" first="Aida B" last="Telegrafi">Aida B. Telegrafi</name><affiliation><nlm:affiliation>GeneDx, Gaithersburg, Maryland, United States of America.</nlm:affiliation></affiliation></author><author><name sortKey="Destree, Anne" sort="Destree, Anne" uniqKey="Destree A" first="Anne" last="Destree">Anne Destree</name><affiliation><nlm:affiliation>Institute of Pathology and Genetics (IPG), Gosselies, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Smigiel, Robert" sort="Smigiel, Robert" uniqKey="Smigiel R" first="Robert" last="Smigiel">Robert Smigiel</name><affiliation><nlm:affiliation>Department of Pediatrics and Rare Disorders, Medical University, Wroclaw, Poland.</nlm:affiliation></affiliation></author><author><name sortKey="Lambie, Lindsday A" sort="Lambie, Lindsday A" uniqKey="Lambie L" first="Lindsday A" last="Lambie">Lindsday A. Lambie</name><affiliation><nlm:affiliation>Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.</nlm:affiliation></affiliation></author><author><name sortKey="Kayserili, Hulya" sort="Kayserili, Hulya" uniqKey="Kayserili H" first="Hülya" last="Kayserili">Hülya Kayserili</name><affiliation><nlm:affiliation>Medical Genetics Department, Koç University School of Medicine (KUSOM), İstanbul, Turkey.</nlm:affiliation></affiliation></author><author><name sortKey="Altunoglu, Umut" sort="Altunoglu, Umut" uniqKey="Altunoglu U" first="Umut" last="Altunoglu">Umut Altunoglu</name><affiliation><nlm:affiliation>Medical Genetics Department, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey.</nlm:affiliation></affiliation></author><author><name sortKey="Lapi, Elisabetta" sort="Lapi, Elisabetta" uniqKey="Lapi E" first="Elisabetta" last="Lapi">Elisabetta Lapi</name><affiliation><nlm:affiliation>Medical Genetics Unit, Anna Meyer Children's University Hospital, Florence, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Uzielli, Maria Luisa" sort="Uzielli, Maria Luisa" uniqKey="Uzielli M" first="Maria Luisa" last="Uzielli">Maria Luisa Uzielli</name><affiliation><nlm:affiliation>University of Florence, Genetic Science, Firenze, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Aracena, Mariana" sort="Aracena, Mariana" uniqKey="Aracena M" first="Mariana" last="Aracena">Mariana Aracena</name><affiliation><nlm:affiliation>División de Pediatría, Pontificia Universidad Católica de Chile and Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago Chile.</nlm:affiliation></affiliation></author><author><name sortKey="Nur, Banu G" sort="Nur, Banu G" uniqKey="Nur B" first="Banu G" last="Nur">Banu G. Nur</name><affiliation><nlm:affiliation>Department of Pediatric Genetics, Akdeniz University Medical School, Antalya, Turkey.</nlm:affiliation></affiliation></author><author><name sortKey="Mihci, Ercan" sort="Mihci, Ercan" uniqKey="Mihci E" first="Ercan" last="Mihci">Ercan Mihci</name><affiliation><nlm:affiliation>Department of Pediatric Genetics, Akdeniz University Medical School, Antalya, Turkey.</nlm:affiliation></affiliation></author><author><name sortKey="Moreira, Lilia M A" sort="Moreira, Lilia M A" uniqKey="Moreira L" first="Lilia M A" last="Moreira">Lilia M A. Moreira</name><affiliation><nlm:affiliation>Laboratory of Human Genetics, Biology Institute, Federal University of Bahia (UFBA), Bahia, Brazil.</nlm:affiliation></affiliation></author><author><name sortKey="Borges Ferreira, Viviane" sort="Borges Ferreira, Viviane" uniqKey="Borges Ferreira V" first="Viviane" last="Borges Ferreira">Viviane Borges Ferreira</name><affiliation><nlm:affiliation>Hospital Santa Izabel, Salvador-Bahia, Brazil.</nlm:affiliation></affiliation></author><author><name sortKey="Horovitz, Dafne D G" sort="Horovitz, Dafne D G" uniqKey="Horovitz D" first="Dafne D G" last="Horovitz">Dafne D G. Horovitz</name><affiliation><nlm:affiliation>CERES-Genetica Reference Center and Studies in Medical Genetics and Instituto Fernandes Figueira / Fiocruz, Rio de Janeiro, Brazil.</nlm:affiliation></affiliation></author><author><name sortKey="Da Rocha, Katia M" sort="Da Rocha, Katia M" uniqKey="Da Rocha K" first="Katia M" last="Da Rocha">Katia M. Da Rocha</name><affiliation><nlm:affiliation>Center for Human Genome Studies, Institute of Biosciences, USP, Sao Paulo, Brazil.</nlm:affiliation></affiliation></author><author><name sortKey="Jezela Stanek, Aleksandra" sort="Jezela Stanek, Aleksandra" uniqKey="Jezela Stanek A" first="Aleksandra" last="Jezela-Stanek">Aleksandra Jezela-Stanek</name><affiliation><nlm:affiliation>Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.</nlm:affiliation></affiliation></author><author><name sortKey="Brooks, Alice S" sort="Brooks, Alice S" uniqKey="Brooks A" first="Alice S" last="Brooks">Alice S. Brooks</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Sophia Children's Hospital, Erasmus MC, Rotterdam, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Reutter, Heiko" sort="Reutter, Heiko" uniqKey="Reutter H" first="Heiko" last="Reutter">Heiko Reutter</name><affiliation><nlm:affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany and Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Cohen, Julie S" sort="Cohen, Julie S" uniqKey="Cohen J" first="Julie S" last="Cohen">Julie S. Cohen</name><affiliation><nlm:affiliation>Division of Neurogenetics, Kennedy Krieger Institute, Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland, United States of America.</nlm:affiliation></affiliation></author><author><name sortKey="Fatemi, Ali" sort="Fatemi, Ali" uniqKey="Fatemi A" first="Ali" last="Fatemi">Ali Fatemi</name><affiliation><nlm:affiliation>Division of Neurogenetics, Kennedy Krieger Institute, Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland, United States of America.</nlm:affiliation></affiliation></author><author><name sortKey="Smitka, Martin" sort="Smitka, Martin" uniqKey="Smitka M" first="Martin" last="Smitka">Martin Smitka</name><affiliation><nlm:affiliation>Abteilung Neuropädiatrie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Grebe, Theresa A" sort="Grebe, Theresa A" uniqKey="Grebe T" first="Theresa A" last="Grebe">Theresa A. Grebe</name><affiliation><nlm:affiliation>Division of Genetics & Metabolism, Phoenix Children's Hospital, Phoenix, Arizona, United States of America.</nlm:affiliation></affiliation></author><author><name sortKey="Di Donato, Nataliya" sort="Di Donato, Nataliya" uniqKey="Di Donato N" first="Nataliya" last="Di Donato">Nataliya Di Donato</name><affiliation><nlm:affiliation>Institute for Clinical Genetics, TU Dresden, Dresden, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Deshpande, Charu" sort="Deshpande, Charu" uniqKey="Deshpande C" first="Charu" last="Deshpande">Charu Deshpande</name><affiliation><nlm:affiliation>Department of Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.</nlm:affiliation></affiliation></author><author><name sortKey="Vandersteen, Anthony" sort="Vandersteen, Anthony" uniqKey="Vandersteen A" first="Anthony" last="Vandersteen">Anthony Vandersteen</name><affiliation><nlm:affiliation>North West Thames Regional Genetics Unit, Kennedy Galton Centre, North West London Hospitals NHS Trust, Northwick Park & St Marks Hospital, Harrow, Middlesex, United Kingdom.</nlm:affiliation></affiliation></author><author><name sortKey="Marques Lourenco, Charles" sort="Marques Lourenco, Charles" uniqKey="Marques Lourenco C" first="Charles" last="Marques Lourenço">Charles Marques Lourenço</name><affiliation><nlm:affiliation>Neurogenetics Unit, Department of Medical Genetics School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.</nlm:affiliation></affiliation></author><author><name sortKey="Dufke, Andreas" sort="Dufke, Andreas" uniqKey="Dufke A" first="Andreas" last="Dufke">Andreas Dufke</name><affiliation><nlm:affiliation>Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Rossier, Eva" sort="Rossier, Eva" uniqKey="Rossier E" first="Eva" last="Rossier">Eva Rossier</name><affiliation><nlm:affiliation>Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Andre, Gwenaelle" sort="Andre, Gwenaelle" uniqKey="Andre G" first="Gwenaelle" last="Andre">Gwenaelle Andre</name><affiliation><nlm:affiliation>Unité de foetopathologie, Hôpital Pellegrin, Place Amélie Raba Léon, Bordeaux, France.</nlm:affiliation></affiliation></author><author><name sortKey="Baumer, Alessandra" sort="Baumer, Alessandra" uniqKey="Baumer A" first="Alessandra" last="Baumer">Alessandra Baumer</name><affiliation><nlm:affiliation>Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.</nlm:affiliation></affiliation></author><author><name sortKey="Spencer, Careni" sort="Spencer, Careni" uniqKey="Spencer C" first="Careni" last="Spencer">Careni Spencer</name><affiliation><nlm:affiliation>Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.</nlm:affiliation></affiliation></author><author><name sortKey="Mcgaughran, Julie" sort="Mcgaughran, Julie" uniqKey="Mcgaughran J" first="Julie" last="Mcgaughran">Julie Mcgaughran</name><affiliation><nlm:affiliation>Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Franke, Lude" sort="Franke, Lude" uniqKey="Franke L" first="Lude" last="Franke">Lude Franke</name><affiliation><nlm:affiliation>University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Veltman, Joris A" sort="Veltman, Joris A" uniqKey="Veltman J" first="Joris A" last="Veltman">Joris A. Veltman</name><affiliation><nlm:affiliation>Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="De Vries, Bert B A" sort="De Vries, Bert B A" uniqKey="De Vries B" first="Bert B A" last="De Vries">Bert B A. De Vries</name><affiliation><nlm:affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Schinzel, Albert" sort="Schinzel, Albert" uniqKey="Schinzel A" first="Albert" last="Schinzel">Albert Schinzel</name><affiliation><nlm:affiliation>Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.</nlm:affiliation></affiliation></author><author><name sortKey="Fisher, Simon E" sort="Fisher, Simon E" uniqKey="Fisher S" first="Simon E" last="Fisher">Simon E. Fisher</name><affiliation><nlm:affiliation>Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Hoischen, Alexander" sort="Hoischen, Alexander" uniqKey="Hoischen A" first="Alexander" last="Hoischen">Alexander Hoischen</name><affiliation><nlm:affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Van Bon, Bregje W" sort="Van Bon, Bregje W" uniqKey="Van Bon B" first="Bregje W" last="Van Bon">Bregje W. Van Bon</name><affiliation><nlm:affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28346496</idno><idno type="pmid">28346496</idno><idno type="doi">10.1371/journal.pgen.1006683</idno><idno type="wicri:Area/PubMed/Corpus">000F89</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000F89</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies.</title><author><name sortKey="Acuna Hidalgo, Rocio" sort="Acuna Hidalgo, Rocio" uniqKey="Acuna Hidalgo R" first="Rocio" last="Acuna-Hidalgo">Rocio Acuna-Hidalgo</name><affiliation><nlm:affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Deriziotis, Pelagia" sort="Deriziotis, Pelagia" uniqKey="Deriziotis P" first="Pelagia" last="Deriziotis">Pelagia Deriziotis</name><affiliation><nlm:affiliation>Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Steehouwer, Marloes" sort="Steehouwer, Marloes" uniqKey="Steehouwer M" first="Marloes" last="Steehouwer">Marloes Steehouwer</name><affiliation><nlm:affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Gilissen, Christian" sort="Gilissen, Christian" uniqKey="Gilissen C" first="Christian" last="Gilissen">Christian Gilissen</name><affiliation><nlm:affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Graham, Sarah A" sort="Graham, Sarah A" uniqKey="Graham S" first="Sarah A" last="Graham">Sarah A. Graham</name><affiliation><nlm:affiliation>Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Van Dam, Sipko" sort="Van Dam, Sipko" uniqKey="Van Dam S" first="Sipko" last="Van Dam">Sipko Van Dam</name><affiliation><nlm:affiliation>University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Hoover Fong, Julie" sort="Hoover Fong, Julie" uniqKey="Hoover Fong J" first="Julie" last="Hoover-Fong">Julie Hoover-Fong</name><affiliation><nlm:affiliation>McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.</nlm:affiliation></affiliation></author><author><name sortKey="Telegrafi, Aida B" sort="Telegrafi, Aida B" uniqKey="Telegrafi A" first="Aida B" last="Telegrafi">Aida B. Telegrafi</name><affiliation><nlm:affiliation>GeneDx, Gaithersburg, Maryland, United States of America.</nlm:affiliation></affiliation></author><author><name sortKey="Destree, Anne" sort="Destree, Anne" uniqKey="Destree A" first="Anne" last="Destree">Anne Destree</name><affiliation><nlm:affiliation>Institute of Pathology and Genetics (IPG), Gosselies, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Smigiel, Robert" sort="Smigiel, Robert" uniqKey="Smigiel R" first="Robert" last="Smigiel">Robert Smigiel</name><affiliation><nlm:affiliation>Department of Pediatrics and Rare Disorders, Medical University, Wroclaw, Poland.</nlm:affiliation></affiliation></author><author><name sortKey="Lambie, Lindsday A" sort="Lambie, Lindsday A" uniqKey="Lambie L" first="Lindsday A" last="Lambie">Lindsday A. Lambie</name><affiliation><nlm:affiliation>Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.</nlm:affiliation></affiliation></author><author><name sortKey="Kayserili, Hulya" sort="Kayserili, Hulya" uniqKey="Kayserili H" first="Hülya" last="Kayserili">Hülya Kayserili</name><affiliation><nlm:affiliation>Medical Genetics Department, Koç University School of Medicine (KUSOM), İstanbul, Turkey.</nlm:affiliation></affiliation></author><author><name sortKey="Altunoglu, Umut" sort="Altunoglu, Umut" uniqKey="Altunoglu U" first="Umut" last="Altunoglu">Umut Altunoglu</name><affiliation><nlm:affiliation>Medical Genetics Department, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey.</nlm:affiliation></affiliation></author><author><name sortKey="Lapi, Elisabetta" sort="Lapi, Elisabetta" uniqKey="Lapi E" first="Elisabetta" last="Lapi">Elisabetta Lapi</name><affiliation><nlm:affiliation>Medical Genetics Unit, Anna Meyer Children's University Hospital, Florence, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Uzielli, Maria Luisa" sort="Uzielli, Maria Luisa" uniqKey="Uzielli M" first="Maria Luisa" last="Uzielli">Maria Luisa Uzielli</name><affiliation><nlm:affiliation>University of Florence, Genetic Science, Firenze, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Aracena, Mariana" sort="Aracena, Mariana" uniqKey="Aracena M" first="Mariana" last="Aracena">Mariana Aracena</name><affiliation><nlm:affiliation>División de Pediatría, Pontificia Universidad Católica de Chile and Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago Chile.</nlm:affiliation></affiliation></author><author><name sortKey="Nur, Banu G" sort="Nur, Banu G" uniqKey="Nur B" first="Banu G" last="Nur">Banu G. Nur</name><affiliation><nlm:affiliation>Department of Pediatric Genetics, Akdeniz University Medical School, Antalya, Turkey.</nlm:affiliation></affiliation></author><author><name sortKey="Mihci, Ercan" sort="Mihci, Ercan" uniqKey="Mihci E" first="Ercan" last="Mihci">Ercan Mihci</name><affiliation><nlm:affiliation>Department of Pediatric Genetics, Akdeniz University Medical School, Antalya, Turkey.</nlm:affiliation></affiliation></author><author><name sortKey="Moreira, Lilia M A" sort="Moreira, Lilia M A" uniqKey="Moreira L" first="Lilia M A" last="Moreira">Lilia M A. Moreira</name><affiliation><nlm:affiliation>Laboratory of Human Genetics, Biology Institute, Federal University of Bahia (UFBA), Bahia, Brazil.</nlm:affiliation></affiliation></author><author><name sortKey="Borges Ferreira, Viviane" sort="Borges Ferreira, Viviane" uniqKey="Borges Ferreira V" first="Viviane" last="Borges Ferreira">Viviane Borges Ferreira</name><affiliation><nlm:affiliation>Hospital Santa Izabel, Salvador-Bahia, Brazil.</nlm:affiliation></affiliation></author><author><name sortKey="Horovitz, Dafne D G" sort="Horovitz, Dafne D G" uniqKey="Horovitz D" first="Dafne D G" last="Horovitz">Dafne D G. Horovitz</name><affiliation><nlm:affiliation>CERES-Genetica Reference Center and Studies in Medical Genetics and Instituto Fernandes Figueira / Fiocruz, Rio de Janeiro, Brazil.</nlm:affiliation></affiliation></author><author><name sortKey="Da Rocha, Katia M" sort="Da Rocha, Katia M" uniqKey="Da Rocha K" first="Katia M" last="Da Rocha">Katia M. Da Rocha</name><affiliation><nlm:affiliation>Center for Human Genome Studies, Institute of Biosciences, USP, Sao Paulo, Brazil.</nlm:affiliation></affiliation></author><author><name sortKey="Jezela Stanek, Aleksandra" sort="Jezela Stanek, Aleksandra" uniqKey="Jezela Stanek A" first="Aleksandra" last="Jezela-Stanek">Aleksandra Jezela-Stanek</name><affiliation><nlm:affiliation>Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.</nlm:affiliation></affiliation></author><author><name sortKey="Brooks, Alice S" sort="Brooks, Alice S" uniqKey="Brooks A" first="Alice S" last="Brooks">Alice S. Brooks</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Sophia Children's Hospital, Erasmus MC, Rotterdam, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Reutter, Heiko" sort="Reutter, Heiko" uniqKey="Reutter H" first="Heiko" last="Reutter">Heiko Reutter</name><affiliation><nlm:affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany and Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Cohen, Julie S" sort="Cohen, Julie S" uniqKey="Cohen J" first="Julie S" last="Cohen">Julie S. Cohen</name><affiliation><nlm:affiliation>Division of Neurogenetics, Kennedy Krieger Institute, Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland, United States of America.</nlm:affiliation></affiliation></author><author><name sortKey="Fatemi, Ali" sort="Fatemi, Ali" uniqKey="Fatemi A" first="Ali" last="Fatemi">Ali Fatemi</name><affiliation><nlm:affiliation>Division of Neurogenetics, Kennedy Krieger Institute, Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland, United States of America.</nlm:affiliation></affiliation></author><author><name sortKey="Smitka, Martin" sort="Smitka, Martin" uniqKey="Smitka M" first="Martin" last="Smitka">Martin Smitka</name><affiliation><nlm:affiliation>Abteilung Neuropädiatrie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Grebe, Theresa A" sort="Grebe, Theresa A" uniqKey="Grebe T" first="Theresa A" last="Grebe">Theresa A. Grebe</name><affiliation><nlm:affiliation>Division of Genetics & Metabolism, Phoenix Children's Hospital, Phoenix, Arizona, United States of America.</nlm:affiliation></affiliation></author><author><name sortKey="Di Donato, Nataliya" sort="Di Donato, Nataliya" uniqKey="Di Donato N" first="Nataliya" last="Di Donato">Nataliya Di Donato</name><affiliation><nlm:affiliation>Institute for Clinical Genetics, TU Dresden, Dresden, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Deshpande, Charu" sort="Deshpande, Charu" uniqKey="Deshpande C" first="Charu" last="Deshpande">Charu Deshpande</name><affiliation><nlm:affiliation>Department of Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.</nlm:affiliation></affiliation></author><author><name sortKey="Vandersteen, Anthony" sort="Vandersteen, Anthony" uniqKey="Vandersteen A" first="Anthony" last="Vandersteen">Anthony Vandersteen</name><affiliation><nlm:affiliation>North West Thames Regional Genetics Unit, Kennedy Galton Centre, North West London Hospitals NHS Trust, Northwick Park & St Marks Hospital, Harrow, Middlesex, United Kingdom.</nlm:affiliation></affiliation></author><author><name sortKey="Marques Lourenco, Charles" sort="Marques Lourenco, Charles" uniqKey="Marques Lourenco C" first="Charles" last="Marques Lourenço">Charles Marques Lourenço</name><affiliation><nlm:affiliation>Neurogenetics Unit, Department of Medical Genetics School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.</nlm:affiliation></affiliation></author><author><name sortKey="Dufke, Andreas" sort="Dufke, Andreas" uniqKey="Dufke A" first="Andreas" last="Dufke">Andreas Dufke</name><affiliation><nlm:affiliation>Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Rossier, Eva" sort="Rossier, Eva" uniqKey="Rossier E" first="Eva" last="Rossier">Eva Rossier</name><affiliation><nlm:affiliation>Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Andre, Gwenaelle" sort="Andre, Gwenaelle" uniqKey="Andre G" first="Gwenaelle" last="Andre">Gwenaelle Andre</name><affiliation><nlm:affiliation>Unité de foetopathologie, Hôpital Pellegrin, Place Amélie Raba Léon, Bordeaux, France.</nlm:affiliation></affiliation></author><author><name sortKey="Baumer, Alessandra" sort="Baumer, Alessandra" uniqKey="Baumer A" first="Alessandra" last="Baumer">Alessandra Baumer</name><affiliation><nlm:affiliation>Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.</nlm:affiliation></affiliation></author><author><name sortKey="Spencer, Careni" sort="Spencer, Careni" uniqKey="Spencer C" first="Careni" last="Spencer">Careni Spencer</name><affiliation><nlm:affiliation>Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.</nlm:affiliation></affiliation></author><author><name sortKey="Mcgaughran, Julie" sort="Mcgaughran, Julie" uniqKey="Mcgaughran J" first="Julie" last="Mcgaughran">Julie Mcgaughran</name><affiliation><nlm:affiliation>Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Franke, Lude" sort="Franke, Lude" uniqKey="Franke L" first="Lude" last="Franke">Lude Franke</name><affiliation><nlm:affiliation>University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Veltman, Joris A" sort="Veltman, Joris A" uniqKey="Veltman J" first="Joris A" last="Veltman">Joris A. Veltman</name><affiliation><nlm:affiliation>Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="De Vries, Bert B A" sort="De Vries, Bert B A" uniqKey="De Vries B" first="Bert B A" last="De Vries">Bert B A. De Vries</name><affiliation><nlm:affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Schinzel, Albert" sort="Schinzel, Albert" uniqKey="Schinzel A" first="Albert" last="Schinzel">Albert Schinzel</name><affiliation><nlm:affiliation>Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.</nlm:affiliation></affiliation></author><author><name sortKey="Fisher, Simon E" sort="Fisher, Simon E" uniqKey="Fisher S" first="Simon E" last="Fisher">Simon E. Fisher</name><affiliation><nlm:affiliation>Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Hoischen, Alexander" sort="Hoischen, Alexander" uniqKey="Hoischen A" first="Alexander" last="Hoischen">Alexander Hoischen</name><affiliation><nlm:affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Van Bon, Bregje W" sort="Van Bon, Bregje W" uniqKey="Van Bon B" first="Bregje W" last="Van Bon">Bregje W. Van Bon</name><affiliation><nlm:affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</nlm:affiliation></affiliation></author></analytic><series><title level="j">PLoS genetics</title><idno type="eISSN">1553-7404</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Abnormalities, Multiple (genetics)</term><term>Abnormalities, Multiple (metabolism)</term><term>Abnormalities, Multiple (pathology)</term><term>Blotting, Western</term><term>Carrier Proteins (genetics)</term><term>Carrier Proteins (metabolism)</term><term>Cell Line</term><term>Cell Proliferation (genetics)</term><term>Cell Transformation, Neoplastic (genetics)</term><term>Child</term><term>Child, Preschool</term><term>Craniofacial Abnormalities (genetics)</term><term>Craniofacial Abnormalities (metabolism)</term><term>Craniofacial Abnormalities (pathology)</term><term>Female</term><term>Gene Expression Profiling</term><term>Genetic Association Studies</term><term>Genetic Predisposition to Disease (genetics)</term><term>Germ-Line Mutation</term><term>HEK293 Cells</term><term>Hand Deformities, Congenital (genetics)</term><term>Hand Deformities, Congenital (metabolism)</term><term>Hand Deformities, Congenital (pathology)</term><term>Hematologic Neoplasms (genetics)</term><term>Hematologic Neoplasms (metabolism)</term><term>Hematologic Neoplasms (pathology)</term><term>Humans</term><term>Infant</term><term>Infant, Newborn</term><term>Intellectual Disability (genetics)</term><term>Intellectual Disability (metabolism)</term><term>Intellectual Disability (pathology)</term><term>Male</term><term>Mutation</term><term>Nails, Malformed (genetics)</term><term>Nails, Malformed (metabolism)</term><term>Nails, Malformed (pathology)</term><term>Nuclear Proteins (genetics)</term><term>Nuclear Proteins (metabolism)</term><term>Phenotype</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Carrier Proteins</term><term>Nuclear Proteins</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Abnormalities, Multiple</term><term>Cell Proliferation</term><term>Cell Transformation, Neoplastic</term><term>Craniofacial Abnormalities</term><term>Genetic Predisposition to Disease</term><term>Hand Deformities, Congenital</term><term>Hematologic Neoplasms</term><term>Intellectual Disability</term><term>Nails, Malformed</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Abnormalities, Multiple</term><term>Carrier Proteins</term><term>Craniofacial Abnormalities</term><term>Hand Deformities, Congenital</term><term>Hematologic Neoplasms</term><term>Intellectual Disability</term><term>Nails, Malformed</term><term>Nuclear Proteins</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Abnormalities, Multiple</term><term>Craniofacial Abnormalities</term><term>Hand Deformities, Congenital</term><term>Hematologic Neoplasms</term><term>Intellectual Disability</term><term>Nails, Malformed</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Blotting, Western</term><term>Cell Line</term><term>Child</term><term>Child, Preschool</term><term>Female</term><term>Gene Expression Profiling</term><term>Genetic Association Studies</term><term>Germ-Line Mutation</term><term>HEK293 Cells</term><term>Humans</term><term>Infant</term><term>Infant, Newborn</term><term>Male</term><term>Mutation</term><term>Phenotype</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">28346496</PMID><DateCreated><Year>2017</Year><Month>03</Month><Day>27</Day></DateCreated><DateCompleted><Year>2017</Year><Month>06</Month><Day>07</Day></DateCompleted><DateRevised><Year>2017</Year><Month>06</Month><Day>07</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Electronic">1553-7404</ISSN><JournalIssue CitedMedium="Internet"><Volume>13</Volume><Issue>3</Issue><PubDate><Year>2017</Year><Month>Mar</Month></PubDate></JournalIssue><Title>PLoS genetics</Title><ISOAbbreviation>PLoS Genet.</ISOAbbreviation></Journal><ArticleTitle>Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies.</ArticleTitle><Pagination><MedlinePgn>e1006683</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1371/journal.pgen.1006683</ELocationID><Abstract><AbstractText>Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Acuna-Hidalgo</LastName><ForeName>Rocio</ForeName><Initials>R</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-9413-0348</Identifier><AffiliationInfo><Affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Deriziotis</LastName><ForeName>Pelagia</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Steehouwer</LastName><ForeName>Marloes</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gilissen</LastName><ForeName>Christian</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Graham</LastName><ForeName>Sarah A</ForeName><Initials>SA</Initials><AffiliationInfo><Affiliation>Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van Dam</LastName><ForeName>Sipko</ForeName><Initials>S</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-9204-0197</Identifier><AffiliationInfo><Affiliation>University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hoover-Fong</LastName><ForeName>Julie</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Telegrafi</LastName><ForeName>Aida B</ForeName><Initials>AB</Initials><AffiliationInfo><Affiliation>GeneDx, Gaithersburg, Maryland, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Destree</LastName><ForeName>Anne</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Institute of Pathology and Genetics (IPG), Gosselies, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Smigiel</LastName><ForeName>Robert</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Department of Pediatrics and Rare Disorders, Medical University, Wroclaw, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lambie</LastName><ForeName>Lindsday A</ForeName><Initials>LA</Initials><AffiliationInfo><Affiliation>Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kayserili</LastName><ForeName>Hülya</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Medical Genetics Department, Koç University School of Medicine (KUSOM), İstanbul, Turkey.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Altunoglu</LastName><ForeName>Umut</ForeName><Initials>U</Initials><AffiliationInfo><Affiliation>Medical Genetics Department, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lapi</LastName><ForeName>Elisabetta</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Medical Genetics Unit, Anna Meyer Children's University Hospital, Florence, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Uzielli</LastName><ForeName>Maria Luisa</ForeName><Initials>ML</Initials><AffiliationInfo><Affiliation>University of Florence, Genetic Science, Firenze, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Aracena</LastName><ForeName>Mariana</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>División de Pediatría, Pontificia Universidad Católica de Chile and Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago Chile.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nur</LastName><ForeName>Banu G</ForeName><Initials>BG</Initials><AffiliationInfo><Affiliation>Department of Pediatric Genetics, Akdeniz University Medical School, Antalya, Turkey.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mihci</LastName><ForeName>Ercan</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Department of Pediatric Genetics, Akdeniz University Medical School, Antalya, Turkey.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Moreira</LastName><ForeName>Lilia M A</ForeName><Initials>LM</Initials><AffiliationInfo><Affiliation>Laboratory of Human Genetics, Biology Institute, Federal University of Bahia (UFBA), Bahia, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Borges Ferreira</LastName><ForeName>Viviane</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Hospital Santa Izabel, Salvador-Bahia, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Horovitz</LastName><ForeName>Dafne D G</ForeName><Initials>DD</Initials><AffiliationInfo><Affiliation>CERES-Genetica Reference Center and Studies in Medical Genetics and Instituto Fernandes Figueira / Fiocruz, Rio de Janeiro, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>da Rocha</LastName><ForeName>Katia M</ForeName><Initials>KM</Initials><AffiliationInfo><Affiliation>Center for Human Genome Studies, Institute of Biosciences, USP, Sao Paulo, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jezela-Stanek</LastName><ForeName>Aleksandra</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brooks</LastName><ForeName>Alice S</ForeName><Initials>AS</Initials><AffiliationInfo><Affiliation>Department of Clinical Genetics, Sophia Children's Hospital, Erasmus MC, Rotterdam, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Reutter</LastName><ForeName>Heiko</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany and Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cohen</LastName><ForeName>Julie S</ForeName><Initials>JS</Initials><AffiliationInfo><Affiliation>Division of Neurogenetics, Kennedy Krieger Institute, Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fatemi</LastName><ForeName>Ali</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Division of Neurogenetics, Kennedy Krieger Institute, Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Smitka</LastName><ForeName>Martin</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Abteilung Neuropädiatrie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Grebe</LastName><ForeName>Theresa A</ForeName><Initials>TA</Initials><AffiliationInfo><Affiliation>Division of Genetics & Metabolism, Phoenix Children's Hospital, Phoenix, Arizona, United States of America.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Di Donato</LastName><ForeName>Nataliya</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Institute for Clinical Genetics, TU Dresden, Dresden, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Deshpande</LastName><ForeName>Charu</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vandersteen</LastName><ForeName>Anthony</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>North West Thames Regional Genetics Unit, Kennedy Galton Centre, North West London Hospitals NHS Trust, Northwick Park & St Marks Hospital, Harrow, Middlesex, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Marques Lourenço</LastName><ForeName>Charles</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Neurogenetics Unit, Department of Medical Genetics School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dufke</LastName><ForeName>Andreas</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rossier</LastName><ForeName>Eva</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Andre</LastName><ForeName>Gwenaelle</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Unité de foetopathologie, Hôpital Pellegrin, Place Amélie Raba Léon, Bordeaux, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Baumer</LastName><ForeName>Alessandra</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Spencer</LastName><ForeName>Careni</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>McGaughran</LastName><ForeName>Julie</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Franke</LastName><ForeName>Lude</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Veltman</LastName><ForeName>Joris A</ForeName><Initials>JA</Initials><AffiliationInfo><Affiliation>Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>De Vries</LastName><ForeName>Bert B A</ForeName><Initials>BB</Initials><AffiliationInfo><Affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schinzel</LastName><ForeName>Albert</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fisher</LastName><ForeName>Simon E</ForeName><Initials>SE</Initials><AffiliationInfo><Affiliation>Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hoischen</LastName><ForeName>Alexander</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van Bon</LastName><ForeName>Bregje W</ForeName><Initials>BW</Initials><Identifier Source="ORCID">http://orcid.org/0000-0003-2234-0105</Identifier><AffiliationInfo><Affiliation>Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>03</Month><Day>27</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>PLoS Genet</MedlineTA><NlmUniqueID>101239074</NlmUniqueID><ISSNLinking>1553-7390</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D002352">Carrier Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D009687">Nuclear Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C425066">SETBP1 protein, human</NameOfSubstance></Chemical></ChemicalList><SupplMeshList><SupplMeshName Type="Disease" UI="C536632">Schinzel-Giedion 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MajorTopicYN="N">Phenotype</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>09</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2017</Year><Month>03</Month><Day>10</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2017</Year><Month>04</Month><Day>10</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2017</Year><Month>3</Month><Day>28</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>6</Month><Day>8</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>3</Month><Day>28</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">28346496</ArticleId><ArticleId IdType="doi">10.1371/journal.pgen.1006683</ArticleId><ArticleId 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