Whole-genome sequencing of quartet families with autism spectrum disorder

被引：378

作者：

Yuen, Ryan K. C. ^{[1
]}

Thiruvahindrapuram, Bhooma ^{[1
]}

Merico, Daniele ^{[1
]}

Walker, Susan ^{[1
]}

Tammimies, Kristiina ^{[2
]}

Hoang, Ny ^{[3
]}

Chrysler, Christina ^{[4
]}

Nalpathamkalam, Thomas ^{[1
]}

Pellecchia, Giovanna ^{[1
]}

Liu, Yi ^{[1
,5
]}

Gazzellone, Matthew J. ^{[1
]}

D'Abate, Lia ^{[1
]}

Deneault, Eric ^{[1
]}

Howe, Jennifer L. ^{[1
]}

Liu, Richard S. C. ^{[1
]}

Thompson, Ann ^{[4
]}

Zarrei, Mehdi ^{[1
]}

Uddin, Mohammed ^{[1
]}

Marshall, Christian R. ^{[1
,6
]}

Ring, Robert H. ^{[7
]}

Zwaigenbaum, Lonnie ^{[8
]}

Ray, Peter N. ^{[6
]}

Weksberg, Rosanna ^{[3
,9
,10
,11
]}

Carter, Melissa T. ^{[12
]}

Fernandez, Bridget A. ^{[13
,14
]}

Roberts, Wendy ^{[12
]}

Szatmari, Peter ^{[12
,15
,16
]}

Scherer, Stephen W. ^{[1
,17
,18
]}

机构：

[1] Hosp Sick Children, Ctr Appl Genom Genet & Genome Biol, Toronto, ON M5G 1X8, Canada

[2] Karolinska Inst, Karolinska Inst KIND, Ctr Neurodev Disorders, Dept Womens & Childrens Hlth,Pediat Neuropsychiat, Stockholm, Sweden

[3] Hosp Sick Children, Dept Pediat, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada

[4] McMaster Univ, Dept Psychiat & Behav Neurosci, Offord Ctr Child Studies, Hamilton, ON, Canada

[5] Shandong Univ, Qilu Childrens Hosp, Jinan Pediat Res Inst, Jinan, Shandong, Peoples R China

[6] Hosp Sick Children, Dept Mol Genet, Toronto, ON M5G 1X8, Canada

[7] Autisrn Speaks, Princeton, NJ USA

[8] Univ Alberta, Dept Pediat, Edmonton, AB, Canada

[9] Hosp Sick Children, Dept Paediat, Toronto, ON M5G 1X8, Canada

[10] Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada

[11] Univ Toronto, Inst Med Sci, Toronto, ON, Canada

[12] Hosp Sick Children, Autism Res Unit, Toronto, ON M5G 1X8, Canada

[13] Mem Univ Newfoundland, Disciplines Genet & Med, St John, NF, Canada

[14] Eastern Hlth, Prov Med Genet Program, St John, NF, Canada

[15] Ctr Addict & Mental Hlth, Child Youth & Family Serv, Toronto, ON, Canada

[16] Univ Toronto, Dept Psychiat, Toronto, ON, Canada

[17] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[18] Univ Toronto, McLaughlin Ctr, Toronto, ON, Canada

来源：

NATURE MEDICINE | 2015年 / 21卷 / 02期

基金：

加拿大健康研究院;

关键词：

FUNCTIONAL IMPACT; RECURRENCE RISK; MUTATIONS; GENES; VARIANTS;

D O I：

10.1038/nm.3792

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：185 / 191

页数：7

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