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Nat Med. 2015 Feb;21(2):185-91. doi: 10.1038/nm.3792. Epub 2015 Jan 26.

Whole-genome sequencing of quartet families with autism spectrum disorder.

Author information

1
The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
2
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.
3
Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
4
Department of Psychiatry and Behavioural Neurosciences, Offord Centre for Child Studies, McMaster University, Hamilton, Ontario, Canada.
5
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.
6
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.
7
Autism Speaks, Princeton, New Jersey, USA.
8
Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
9
Department of Molecular Genetics, Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
10
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.
11
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.
12
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.
13
Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario, Canada.
14
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.
15
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.

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.

Comment in

PMID:
25621899
DOI:
10.1038/nm.3792
[Indexed for MEDLINE]

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