Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism.
Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism.
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DOI：
10.1371/journal.pgen.1002635
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Walsh CA
中科院分区：
文献类型：
--
作者：
Chahrour MH;Yu TW;Lim ET;Ataman B;Coulter ME;Hill RS;Stevens CR;Schubert CR;ARRA Autism Sequencing Collaboration;Greenberg ME;Gabriel SB;Walsh CA
尽管自闭症具有明显的遗传成分，但该疾病的高度遗传异质性一直是识别致病基因的挑战。我们使用纯合性分析来识别来自非近亲家庭的先证者，这些先证者显示出遥远的共同祖先的证据，表明潜在的隐性突变。对 16 个先证者的全外显子组测序揭示了经过验证的纯合性、潜在致病性隐性突变，这些突变与 4/16 个家族的疾病完美分离。候选基因（UBE3B、CLTCL1、NCKAP5L、ZNF18）编码参与蛋白水解、GTP酶介导的信号传导、细胞骨架组织和其他途径的蛋白质。此外，神经元去极化调节这些基因的转录，表明神经元中潜在的活动依赖性作用。我们提出了一种多维策略，用于过滤全外显子组序列数据，以寻找自闭症的候选隐性突变，这可能对其他复杂的异质性疾病具有更广泛的适用性。自闭症谱系障碍是一种遗传高度异质性的神经发育障碍，没有一个基因占病例的比例超过 1%。为了识别隐性突变，我们根据基因组中纯合性的丰度从远交群体中选择了先证者。我们询问了 16 个先证者的整个编码序列，这些先证者有父母共同祖先的证据，并确定了四个候选自闭症基因。此外，这些基因的表达对神经元活动有反应。我们提出了一种识别遗传复杂疾病中候选隐性突变的策略。
Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders. Autism spectrum disorders are neurodevelopmental disorders that are genetically highly heterogeneous, with no single gene accounting for more than 1% of cases. In order to identify recessive mutations, we selected probands from an outbred population based on abundance of homozygosity in their genomes. We interrogated the entire coding sequences of 16 probands that had evidence of parental shared ancestry and identified four candidate autism genes. Furthermore, the expression of these genes was responsive to neuronal activity. We present a strategy for identifying candidate recessive mutations in genetically complex disorders.
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影响因子：
56.9
作者：
Morrow, Eric M.;Yoo, Seung-Yun;Flavell, Steven W.;Kim, Tae-Kyung;Lin, Yingxi;Hill, Robert Sean;Mukaddes, Nahit M.;Balkhy, Soher;Gascon, Generoso;Hashmi, Asif;Al-Saad, Samira;Ware, Janice;Joseph, Robert M.;Greenblatt, Rachel;Gleason, Danielle;Ertelt, Julia A.;Apse, Kira A.;Bodell, Adria;Partlow, Jennifer N.;Barry, Brenda;Yao, Hui;Markianos, Kyriacos;Ferland, Russell J.;Greenberg, Michael E.;Walsh, Christopher A.
通讯作者：
Walsh, Christopher A.
影响因子：
16.2
作者：
Flavell, Steven W.;Kim, Tae-Kyung;Gray, Jesse M.;Harmin, David A.;Hemberg, Martin;Hong, Elizabeth J.;Markenscoff-Papadimitriou, Eirene;Bear, Daniel M.;Greenberg, Michael E.
通讯作者：
Greenberg, Michael E.
影响因子：
3.9
作者：
Monnier, N;Satre, V;Lunardi, J
通讯作者：
Lunardi, J
影响因子：
30.8
作者：
Krawitz, Peter M.;Schweiger, Michal R.;Robinson, Peter N.
通讯作者：
Robinson, Peter N.
影响因子：
4
作者：
Hoodfar, E;Teebi, AS
通讯作者：
Teebi, AS