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Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.
Wang, Tianyun; Hoekzema, Kendra; Vecchio, Davide; Wu, Huidan; Sulovari, Arvis; Coe, Bradley P; Gillentine, Madelyn A; Wilfert, Amy B; Perez-Jurado, Luis A; Kvarnung, Malin; Sleyp, Yoeri; Earl, Rachel K; Rosenfeld, Jill A; Geisheker, Madeleine R; Han, Lin; Du, Bing; Barnett, Chris; Thompson, Elizabeth; Shaw, Marie; Carroll, Renee; Friend, Kathryn; Catford, Rachael; Palmer, Elizabeth E; Zou, Xiaobing; Ou, Jianjun; Li, Honghui; Guo, Hui; Gerdts, Jennifer; Avola, Emanuela; Calabrese, Giuseppe; Elia, Maurizio; Greco, Donatella; Lindstrand, Anna; Nordgren, Ann; Anderlid, Britt-Marie; Vandeweyer, Geert; Van Dijck, Anke; Van der Aa, Nathalie; McKenna, Brooke; Hancarova, Miroslava; Bendova, Sarka; Havlovicova, Marketa; Malerba, Giovanni; Bernardina, Bernardo Dalla; Muglia, Pierandrea; van Haeringen, Arie; Hoffer, Mariette J V; Franke, Barbara; Cappuccio, Gerarda; Delatycki, Martin.
Afiliação
  • Wang T; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Hoekzema K; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Vecchio D; Rare Disease and Medical Genetics, Academic Department of Pediatrics, Bambino Gesù Children's Hospital, Rome, Italy.
  • Wu H; Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Rome, Italy.
  • Sulovari A; Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
  • Coe BP; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Gillentine MA; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Wilfert AB; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Perez-Jurado LA; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Kvarnung M; Paediatric and Reproductive Genetics unit, Women's and Children's Hospital, Adelaide, SA, Australia.
  • Sleyp Y; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
  • Earl RK; Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM) and CIBERER, Barcelona, Spain.
  • Rosenfeld JA; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Geisheker MR; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
  • Han L; Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium.
  • Du B; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
  • Barnett C; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Thompson E; Baylor Genetics, Houston, TX, USA.
  • Shaw M; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Carroll R; Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
  • Friend K; Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
  • Catford R; Paediatric and Reproductive Genetics unit, Women's and Children's Hospital, Adelaide, SA, Australia.
  • Palmer EE; Adelaide Medical School and the Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia.
  • Zou X; Paediatric and Reproductive Genetics unit, Women's and Children's Hospital, Adelaide, SA, Australia.
  • Ou J; Adelaide Medical School and the Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia.
  • Li H; Adelaide Medical School and the Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia.
  • Guo H; Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
  • Gerdts J; Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
  • Avola E; Genetics of Learning Disability Service, Hunter New England Health Service, Waratah, NSW, Australia.
  • Calabrese G; School of Women's and Children's Health, University of New South Wales, Randwick, NSW, Australia.
  • Elia M; Children Development Behavior Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • Greco D; Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, China.
  • Lindstrand A; Key Laboratory of Developmental Disorders in Children, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, China.
  • Nordgren A; Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
  • Anderlid BM; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
  • Vandeweyer G; Oasi Research Institute-IRCCS, Troina, Italy.
  • Van Dijck A; Oasi Research Institute-IRCCS, Troina, Italy.
  • Van der Aa N; Oasi Research Institute-IRCCS, Troina, Italy.
  • McKenna B; Oasi Research Institute-IRCCS, Troina, Italy.
  • Hancarova M; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Bendova S; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
  • Havlovicova M; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Malerba G; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
  • Bernardina BD; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Muglia P; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
  • van Haeringen A; Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
  • Hoffer MJV; Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
  • Franke B; Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
  • Cappuccio G; Department of Psychology, Emory University, Atlanta, GA, USA.
  • Delatycki M; Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
Nat Commun ; 11(1): 4932, 2020 10 01.
Article em En | MEDLINE | ID: mdl-33004838
Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Predisposição Genética para Doença / Transtornos do Neurodesenvolvimento Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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XML
PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Predisposição Genética para Doença / Transtornos do Neurodesenvolvimento Idioma: En Ano de publicação: 2020 Tipo de documento: Article