title: Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.
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.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Holly A F
authors.identifier: http://orcid.org/0000-0002-0764-3493
authors.initials: HA
authors.lastname: Stessman
authors.affiliation: 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.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiong
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Coe
authors.affiliation: State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
authors.forename: Tianyun
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Kendra
authors.initials: K
authors.lastname: Hoekzema
authors.affiliation: 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.
authors.forename: Michaela
authors.initials: M
authors.lastname: Fenckova
authors.affiliation: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Kvarnung
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gerdts
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Trinh
authors.affiliation: Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: Cosemans
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Vives
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Tychele N
authors.initials: TN
authors.lastname: Turner
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Gijs
authors.initials: G
authors.lastname: Santen
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ruivenkamp
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Kriek
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Arie
authors.initials: A
authors.lastname: van Haeringen
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
authors.forename: Emmelien
authors.initials: E
authors.lastname: Aten
authors.affiliation: 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.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Friend
authors.affiliation: South Australian Clinical Genetics Service, SA Pathology (at the Women's and Children's Hospital), Adelaide, South Australia, Australia.
authors.forename: Jan
authors.initials: J
authors.lastname: Liebelt
authors.affiliation: South Australian Clinical Genetics Service, SA Pathology (at the Women's and Children's Hospital), Adelaide, South Australia, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Barnett
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Haan
authors.affiliation: School of Medicine and the Robinson Research Institute, the University of Adelaide at the Women's and Children's Hospital, Adelaide, South Australia, Australia.
authors.forename: Marie
authors.initials: M
authors.lastname: Shaw
authors.affiliation: 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.
authors.forename: Jozef
authors.identifier: http://orcid.org/0000-0002-7884-6861
authors.initials: J
authors.lastname: Gecz
authors.affiliation: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Anderlid
authors.affiliation: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Nordgren
authors.affiliation: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Lindstrand
authors.affiliation: Center for Molecular Studies, J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Schwartz
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: R Frank
authors.identifier: http://orcid.org/0000-0003-2024-0485
authors.initials: RF
authors.lastname: Kooy
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Vandeweyer
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: Celine
authors.initials: C
authors.lastname: Helsmoortel
authors.affiliation: Unit of Pediatrics &Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
authors.forename: Corrado
authors.identifier: http://orcid.org/0000-0003-1049-0683
authors.initials: C
authors.lastname: Romano
authors.affiliation: Unit of Pediatrics &Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Alberti
authors.affiliation: Laboratory of Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Vinci
authors.affiliation: Unit of Pediatrics &Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Avola
authors.affiliation: Unit of Neurology, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Giusto
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Courchesne
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Pramparo
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Pierce
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Nalabolu
authors.affiliation: MIND Institute and the University of California Davis School of Medicine, Sacramento, California, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Amaral
authors.affiliation: 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.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: 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.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Delatycki
authors.affiliation: 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.
authors.forename: Paul J
authors.identifier: http://orcid.org/0000-0003-2531-8413
authors.initials: PJ
authors.lastname: Lockhart
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, California, USA.
authors.forename: Fereydoun
authors.initials: F
authors.lastname: Hormozdiari
authors.affiliation: 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.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Harich
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Castells-Nobau
authors.affiliation: State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Xia
authors.affiliation: Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Peeters
authors.affiliation: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.affiliation: 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.
authors.forename: Annette
authors.initials: A
authors.lastname: Schenck
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Bernier
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.|Howard Hughes Medical Institute, Seattle, Washington, USA.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D010641:Phenotype