De novo and inherited private variants in MAP1B in periventricular nodular heterotopia

被引：49

作者：

Heinzen, Erin L. ^{[1
]}

O'Neill, Adam C. ^{[2
]}

Zhu, Xiaolin ^{[1
]}

Allen, Andrew S. ^{[3
,4
]}

Bahlo, Melanie ^{[5
,6
]}

Chelly, Jamel ^{[7
,8
]}

Chen, Ming Hui ^{[9
,10
]}

Dobyns, William B. ^{[11
,12
,13
]}

Freytag, Saskia ^{[14
]}

Guerrini, Renzo ^{[15
]}

Leventer, Richard J. ^{[16
,17
,18
]}

Poduri, Annapurna ^{[19
]}

Robertson, Stephen P. ^{[2
]}

Walsh, Christopher A. ^{[20
,21
,22
,23
,24
]}

Zhang, Mengqi ^{[4
,25
]}

机构：

[1] Columbia Univ, Med Ctr, Inst Genom Med, New York, NY 10032 USA

[2] Univ Otago, Dunedin Sch Med, Dept Womens & Childrens Hlth, Dunedin, New Zealand

[3] Duke Univ, Med Ctr, Ctr Stat Genet & Genom, Durham, NC USA

[4] Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA

[5] Walter & Eliza Hall Inst Med Res, Populat Hlth & Immun Div, Parkville, Vic, Australia

[6] Univ Melbourne, Sch Math & Stat, Dept Med Biol, Parkville, Vic, Australia

[7] Hop Univ Strasbourg, Pole Biol, Strasbourg, France

[8] Univ Strasbourg, IGBMC, INSERM, U964,CNRS,UMR 7104, Illkirch Graffenstaden, France

[9] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA

[10] Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA

[11] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

[12] Univ Washington, Dept Neurol, Seattle, WA 98195 USA

[13] Seattle Childrens Res Inst, Ctr Integrat Brain Res, Seattle, WA USA

[14] Univ Melbourne, Dept Med Biol, Parkville, Vic, Australia

[15] Univ Florence, Childrens Hosp Anna Meyer, Dept Neurosci, Florence, Italy

[16] Univ Melbourne, Royal Childrens Hosp, Dept Neurol, Parkville, Vic, Australia

[17] Univ Melbourne, Murdoch Childrens Res Inst, Parkville, Vic, Australia

[18] Univ Melbourne, Dept Pediat, Parkville, Vic, Australia

[19] Boston Childrens Hosp, Dept Neurol, Div Epilepsy & Clin Neurophysiol, Boston, MA USA

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

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

[22] Harvard Med Sch, Dept Pediat, Boston, MA USA

[23] Harvard Med Sch, Dept Neurol, Boston, MA USA

[24] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA

[25] Duke Univ, Program Computat Biol & Bioinformat, Durham, NC USA

来源：

PLOS GENETICS | 2018年 / 14卷 / 05期

基金：

澳大利亚国家健康与医学研究理事会; 美国国家卫生研究院;

关键词：

FRAGILE-X-SYNDROME; CORTICAL DEVELOPMENT; DEVELOPMENTAL DISORDERS; NEURONAL MIGRATION; MICROARRAY DATA; DOUBLE CORTEX; HUMAN BRAIN; MUTATIONS; GENE; MALFORMATIONS;

D O I：

10.1371/journal.pgen.1007281

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Periventricular nodular heterotopia (PVNH) is a malformation of cortical development commonly associated with epilepsy. We exome sequenced 202 individuals with sporadic PVNH to identify novel genetic risk loci. We first performed a trio-based analysis and identified 219 de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27x10(-7)), suggesting a role for rare new alleles in genes yet to be associated with the condition. Using a gene-level collapsing analysis comparing cases and controls, we identified a genome-wide significant signal driven by four ultrarare loss-of-function heterozygous variants in MAP1B, including one de novo variant. In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH. The PVNH was frontally predominant and associated with perisylvian polymicrogyria. These results implicate MAP1B in PVNH. More broadly, our findings suggest that detrimental mutations likely arising in immediately preceding generations with incomplete penetrance may also be responsible for some apparently sporadic diseases.

引用

页数：23

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