title: Whole-genome sequencing of quartet families with autism spectrum disorder.
abstract: Autism spectrum disorder (ASD) is genetically heterogeneous, with evidence for hundreds of susceptibility loci. Previous microarray and exome-sequencing studies have examined portions of the genome in simplex families (parents and one ASD-affected child) having presumed sporadic forms of the disorder. We used whole-genome sequencing (WGS) of 85 quartet families (parents and two ASD-affected siblings), consisting of 170 individuals with ASD, to generate a comprehensive data resource encompassing all classes of genetic variation (including noncoding variants) and accompanying phenotypes, in apparently familial forms of ASD. By examining de novo and rare inherited single-nucleotide and structural variations in genes previously reported to be associated with ASD or other neurodevelopmental disorders, we found that some (69.4%) of the affected siblings carried different ASD-relevant mutations. These siblings with discordant mutations tended to demonstrate more clinical variability than those who shared a risk variant. Our study emphasizes that substantial genetic heterogeneity exists in ASD, necessitating the use of WGS to delineate all genic and non-genic susceptibility variants in research and in clinical diagnostics.
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Ryan K C
authors.initials: RK
authors.lastname: Yuen
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, 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, Ontario, Canada.
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Walker
authors.affiliation: 1] The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Women's and Children's Health, Pediatric Neuropsychiatry Unit, Center of Neurodevelopmental Disorders at Karolinska Institutet (KIND), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Tammimies
authors.affiliation: Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ny
authors.initials: N
authors.lastname: Hoang
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, Offord Centre for Child Studies, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Chrysler
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, 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, Ontario, Canada.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pellecchia
authors.affiliation: 1] The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Jinan Pediatric Research Institute, Qilu Children's Hospital of Shandong University, Shandong, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gazzellone
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, 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, Ontario, 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, Ontario, Canada.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Howe
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Richard S C
authors.initials: RS
authors.lastname: Liu
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, Offord Centre for Child Studies, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Ann
authors.initials: A
authors.lastname: Thompson
authors.affiliation: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, 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, Ontario, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Uddin
authors.affiliation: 1] The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Molecular Genetics, Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: Autism Speaks, Princeton, New Jersey, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Ring
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Lonnie
authors.initials: L
authors.lastname: Zwaigenbaum
authors.affiliation: Department of Molecular Genetics, Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Ray
authors.affiliation: 1] Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. [2] Department of Paediatrics and Genetics and Genome Biology Program, The Hospital for Sick Children and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.affiliation: 1] Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. [2] Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Melissa T
authors.initials: MT
authors.lastname: Carter
authors.affiliation: 1] Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada. [2] Provincial Medical Genetic Program, Eastern Health, St. John's, Newfoundland, Canada.
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Fernandez
authors.affiliation: Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Wendy
authors.initials: W
authors.lastname: Roberts
authors.affiliation: 1] Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Child Youth and Family Services, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. [3] Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Szatmari
authors.affiliation: 1] The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
mesh_terms: D000328:Adult; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D010290:Parents; D017422:Sequence Analysis, DNA; D035781:Siblings