Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms

被引：116

作者：

D'Gama, Alissa M. ^{[1
,2
,3
,4
,5
]}

Pochareddy, Sirisha ^{[6
,7
,8
,9
]}

Li, Mingfeng ^{[6
,7
,8
,9
]}

Jamuar, Saumya S. ^{[1
,2
,3
,4
,5
,10
,11
]}

Reiff, Rachel E. ^{[1
,2
,3
,4
,5
]}

Lam, Anh-Thu N. ^{[1
,2
,3
,4
,5
]}

Sestan, Nenad ^{[6
,7
,8
,9
]}

Walsh, Christopher A. ^{[1
,2
,3
,4
,5
]}

机构：

[1] Boston Childrens Hosp, Div Genet & Genom, Manton Ctr Orphan Dis, Boston, MA 02115 USA

[2] Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA

[5] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[6] Yale Univ, Sch Med, Dept Neurosci, New Haven, CT 06510 USA

[7] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA

[8] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA

[9] Yale Univ, Sch Med, Kavli Inst Neurosci, New Haven, CT 06510 USA

[10] KK Womens & Childrens Hosp, Dept Paediat, Singapore, Singapore

[11] Duke NUS Grad Sch Med, Paediatr Acad Clin Programme, Singapore, Singapore

来源：

NEURON | 2015年 / 88卷 / 05期

关键词：

DE-NOVO MUTATIONS; SOMATIC MUTATIONS; DRAVET SYNDROME; MALFORMATIONS; SCN1A; AKT3;

D O I：

10.1016/j.neuron.2015.11.009

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Single nucleotide variants (SNVs), particularly loss-of-function mutations, are significant contributors to autism spectrum disorder (ASD) risk. Here we report the first systematic deep sequencing study of 55 postmortem ASD brains for SNVs in 78 known ASD candidate genes. Remarkably, even without parental samples, we find more ASD brains with mutations that are protein-altering (26/55 cases versus 12/50 controls, p = 0.015), deleterious (16/55 versus 5/50, p = 0.016), or loss-of-function (6/55 versus 0/50, p = 0.028) compared to controls, with recurrent deleterious mutations in ARID1B, SCN1A, SCN2A, and SETD2, suggesting these mutations contribute to ASD risk. In several cases, the identified mutations and medical records suggest syndromic ASD diagnoses. Two ASD and one Fragile X premutation case showed deleterious somatic mutations, providing evidence that somatic mutations occur in ASD cases, and supporting a model in which a combination of germline and/or somatic mutations may contribute to ASD risk on a case-by-case basis.

引用

页码：910 / 917

页数：8

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