title: Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.
abstract: We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10-4). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Ryan K
authors.identifier: http://orcid.org/0000-0001-7273-4968
authors.initials: RK
authors.lastname: C Yuen
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Deep Genomics Inc., Toronto, Canada.
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.affiliation: Google, Mountain View, California, USA.|Verily Life Sciences, South San Francisco, California, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Bookman
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: L Howe
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Bhooma
authors.initials: B
authors.lastname: Thiruvahindrapuram
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Rohan V
authors.initials: RV
authors.lastname: Patel
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Joe
authors.initials: J
authors.lastname: Whitney
authors.affiliation: Google, Mountain View, California, USA.|Verily Life Sciences, South San Francisco, California, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Deflaux
authors.affiliation: Google, Mountain View, California, USA.|Verily Life Sciences, South San Francisco, California, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bingham
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Zhuozhi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pellecchia
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Buchanan
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Walker
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Uddin
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Zarrei
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Deneault
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Lia
authors.initials: L
authors.lastname: D'Abate
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Ada J S
authors.initials: AJ
authors.lastname: Chan
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Koyanagi
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Tara
authors.initials: T
authors.lastname: Paton
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Sergio L
authors.initials: SL
authors.lastname: Pereira
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Autism Research Unit, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Ny
authors.initials: N
authors.lastname: Hoang
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Worrawat
authors.initials: W
authors.lastname: Engchuan
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Higginbotham
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Ho
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Lamoureux
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Weili
authors.initials: W
authors.lastname: Li
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Jeffrey R
authors.identifier: http://orcid.org/0000-0001-5058-2393
authors.initials: JR
authors.lastname: MacDonald
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nalpathamkalam
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Wilson W L
authors.initials: WW
authors.lastname: Sung
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Tsoi
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Wei
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Lizhen
authors.initials: L
authors.lastname: Xu
authors.affiliation: Public Population Project in Genomics and Society, McGill University, Montreal, Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Tasse
authors.affiliation: Public Population Project in Genomics and Society, McGill University, Montreal, Canada.
authors.forename: Emily
authors.initials: E
authors.lastname: Kirby
authors.affiliation: BioTeam Inc., Middleton, Massachusetts, USA.
authors.forename: William
authors.initials: W
authors.lastname: Van Etten
authors.affiliation: BioTeam Inc., Middleton, Massachusetts, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Twigger
authors.affiliation: Autism Research Unit, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Wendy
authors.initials: W
authors.lastname: Roberts
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Autism Research Unit, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Irene
authors.initials: I
authors.lastname: Drmic
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Autism Research Unit, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Sanne
authors.initials: S
authors.lastname: Jilderda
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Autism Research Unit, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Bonnie MacKinnon
authors.initials: BM
authors.lastname: Modi
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kellam
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Dalla Lana School of Public Health and the Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Szego
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Canada.|Dalla Lana School of Public Health and the Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Cytrynbaum
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Canada.|Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Canada.
authors.forename: Lonnie
authors.initials: L
authors.lastname: Zwaigenbaum
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Woodbury-Smith
authors.affiliation: Bloorview Research Institute, University of Toronto, Toronto, Canada. .
authors.forename: Jessica
authors.initials: J
authors.lastname: Brian
authors.affiliation: Bloorview Research Institute, University of Toronto, Toronto, Canada. .
authors.forename: Lili
authors.initials: L
authors.lastname: Senman
authors.affiliation: Bloorview Research Institute, University of Toronto, Toronto, Canada. .
authors.forename: Alana
authors.initials: A
authors.lastname: Iaboni
authors.affiliation: Bloorview Research Institute, University of Toronto, Toronto, Canada. .
authors.forename: Krissy
authors.initials: K
authors.lastname: Doyle-Thomas
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada.
authors.forename: Ann
authors.initials: A
authors.lastname: Thompson
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Chrysler
authors.affiliation: Bloorview Research Institute, University of Toronto, Toronto, Canada. .
authors.forename: Jonathan
authors.initials: J
authors.lastname: Leef
authors.affiliation: Department of Psychiatry, McGill University, Montreal, Canada.
authors.forename: Tal
authors.initials: T
authors.lastname: Savion-Lemieux
authors.affiliation: Departments of Pediatrics and of Psychology &Neuroscience, Dalhousie University and Autism Research Centre, IWK Health Centre, Halifax, Canada.
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Smith
authors.affiliation: Department of Psychiatry, Queen's University, Kinston, Canada.
authors.forename: Xudong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Children's Health Research Institute, London, Ontario, Canada.|Western University, London, Ontario, Canada.
authors.forename: Rob
authors.initials: R
authors.lastname: Nicolson
authors.affiliation: Autism Speaks, New York, New York, USA.
authors.forename: Vicki
authors.initials: V
authors.lastname: Seifer
authors.affiliation: Autism Speaks, New York, New York, USA.
authors.forename: Angie
authors.initials: A
authors.lastname: Fedele
authors.affiliation: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Edwin H
authors.identifier: http://orcid.org/0000-0002-5848-5114
authors.initials: EH
authors.lastname: Cook
authors.affiliation: Department of Radiology, University of Washington, Seattle, Washington, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Dager
authors.affiliation: Department of Speech and Hearing Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Estes
authors.affiliation: Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Louise
authors.initials: L
authors.lastname: Gallagher
authors.affiliation: Sleep Disorders Division, Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Malow
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Parr
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Spence
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Jacob
authors.initials: J
authors.lastname: Vorstman
authors.affiliation: Deep Genomics Inc., Toronto, Canada.|Department of Electrical and Computer Engineering and Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Canada.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Frey
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Robinson
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Canada.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Strug
authors.affiliation: Disciplines of Genetics and Medicine, Memorial University of Newfoundland and Provincial Medical Genetic Program, Eastern Health, St. John's, Canada.
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Fernandez
authors.affiliation: Department of Psychiatry, McGill University, Montreal, Canada.
authors.forename: Mayada
authors.initials: M
authors.lastname: Elsabbagh
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada.|Regional Genetics Program, The Children's Hospital of Eastern Ontario, Ottawa, Canada.
authors.forename: Melissa T
authors.initials: MT
authors.lastname: Carter
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Hallmayer
authors.affiliation: Centre of Genomics and Policy, McGill University, Montreal, Canada.
authors.forename: Bartha M
authors.initials: BM
authors.lastname: Knoppers
authors.affiliation: Bloorview Research Institute, University of Toronto, Toronto, Canada. .
authors.forename: Evdokia
authors.initials: E
authors.lastname: Anagnostou
authors.affiliation: Child Youth and Family Services, Centre for Addiction and Mental Health, Toronto, Canada.|Department of Psychiatry, University of Toronto, Toronto, Canada.|Department of Psychiatry, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Szatmari
authors.affiliation: Department of Pharmacology &Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Robert H
authors.identifier: http://orcid.org/0000-0002-7037-4409
authors.initials: RH
authors.lastname: Ring
authors.affiliation: Google, Mountain View, California, USA.|Verily Life Sciences, South San Francisco, California, USA.
authors.forename: David
authors.identifier: http://orcid.org/0000-0002-6407-8646
authors.initials: D
authors.lastname: Glazer
authors.affiliation: Autism Speaks, New York, New York, USA.
authors.forename: Mathew T
authors.initials: MT
authors.lastname: Pletcher
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.|McLaughlin Centre, University of Toronto, Toronto, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics*; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D016254:Mutagenesis, Insertional / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics