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PMID: 28191889 Published · ppublish English Journal Article

Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.

Nature genetics ·Vol. 49 ·No. 4 ·2017-04-00 ·Pages 515-526

Stessman HA, Xiong B, Coe BP, Wang T, Hoekzema K, Fenckova M, Kvarnung M, Gerdts J, Trinh S, Cosemans N, Vives L, Lin J, Turner TN, Santen G, Ruivenkamp C, Kriek M, van Haeringen A, Aten E, Friend K, Liebelt J, Barnett C, Haan E, Shaw M, Gecz J, Anderlid BM, Nordgren A, Lindstrand A, Schwartz C, Kooy RF, Vandeweyer G, Helsmoortel C, Romano C, Alberti A, Vinci M, Avola E, Giusto S, Courchesne E, Pramparo T, Pierce K, Nalabolu S, Amaral DG, Scheffer IE, Delatycki MB, Lockhart PJ, Hormozdiari F, Harich B, Castells-Nobau A, Xia K, Peeters H, Nordenskjöld M, Schenck A, Bernier RA, Eichler EE

Abstract

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.

MeSH Terms
Autistic Disorder/genetics Developmental Disabilities/genetics Female Humans Intellectual Disability/genetics Male Mutation/genetics Phenotype
Authors & Affiliations
53 authors, click to expand affiliations / ORCID
Stessman Holly A F ORCID
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
Xiong Bo
Department of Genome Sciences, University of Washington, Seattle, Washington, USA. | Department of Forensic Medicine and Institute of Brain Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Coe Bradley P
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
Wang Tianyun
State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Hoekzema Kendra
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
Fenckova Michaela
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. | Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
Kvarnung Malin
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. | Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Gerdts Jennifer
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
Trinh Sandy
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
Cosemans Nele
Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium.
Vives Laura
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
Lin Janice
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
Turner Tychele N
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
Santen Gijs
Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
Ruivenkamp Claudia
Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
Kriek Marjolein
Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
van Haeringen Arie
Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
Aten Emmelien
Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
Friend Kathryn
School of Medicine and the Robinson Research Institute, the University of Adelaide at the Women's and Children's Hospital, Adelaide, South Australia, Australia. | Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia.
Liebelt Jan
South Australian Clinical Genetics Service, SA Pathology (at the Women's and Children's Hospital), Adelaide, South Australia, Australia.
Barnett Christopher
South Australian Clinical Genetics Service, SA Pathology (at the Women's and Children's Hospital), Adelaide, South Australia, Australia.
Haan Eric
School of Medicine and the Robinson Research Institute, the University of Adelaide at the Women's and Children's Hospital, Adelaide, South Australia, Australia. | South Australian Clinical Genetics Service, SA Pathology (at the Women's and Children's Hospital), Adelaide, South Australia, Australia.
Shaw Marie
School of Medicine and the Robinson Research Institute, the University of Adelaide at the Women's and Children's Hospital, Adelaide, South Australia, Australia.
Gecz Jozef ORCID
School of Medicine and the Robinson Research Institute, the University of Adelaide at the Women's and Children's Hospital, Adelaide, South Australia, Australia. | Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia. | South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
Anderlid Britt-Marie
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. | Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Nordgren Ann
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. | Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Lindstrand Anna
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. | Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Schwartz Charles
Center for Molecular Studies, J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, USA.
Kooy R Frank ORCID
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Vandeweyer Geert
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Helsmoortel Celine
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Romano Corrado ORCID
Unit of Pediatrics &Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
Alberti Antonino
Unit of Pediatrics &Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
Vinci Mirella
Laboratory of Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
Avola Emanuela
Unit of Pediatrics &Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
Giusto Stefania
Unit of Neurology, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
Courchesne Eric
Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, California, USA.
Pramparo Tiziano
Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, California, USA.
Pierce Karen
Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, California, USA.
Nalabolu Srinivasa
Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, California, USA.
Amaral David G
MIND Institute and the University of California Davis School of Medicine, Sacramento, California, USA.
Scheffer Ingrid E
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia. | Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia. | Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
Delatycki Martin B
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia. | Victorian Clinical Genetics Services, Parkville, Victoria, Australia. | Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
Lockhart Paul J ORCID
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia. | Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
Hormozdiari Fereydoun
Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, California, USA.
Harich Benjamin
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. | Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
Castells-Nobau Anna
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. | Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
Xia Kun
State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Peeters Hilde
Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium.
Nordenskjöld Magnus
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. | Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Schenck Annette
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. | Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
Bernier Raphael A
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
Eichler Evan E
Department of Genome Sciences, University of Washington, Seattle, Washington, USA. | Howard Hughes Medical Institute, Seattle, Washington, USA.
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.3792
Published
2017-04-00
Epub
2017-00-13
Pages
515-526
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC5374041
Subset
IM
Grants
NIMH NIH HHS · U24 MH081810 · United States
NCATS NIH HHS · KL2 TR000099 · United States
NICHD NIH HHS · U54 HD083091 · United States
NIH HHS · P40 OD018537 · United States
NHGRI NIH HHS · T32 HG000035 · United States
NCATS NIH HHS · KL2 TR001444 · United States
Howard Hughes Medical Institute · United States
NIMH NIH HHS · R01 MH101221 · United States
External Links
PubMed source DOI: 10.1038/ng.3792 PMC Full Text View journal details
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