Exome sequencing of 85 Williams-Beuren syndrome cases rules out coding variation as a major contributor to remaining variance in social behavior.
Exome sequencing of 85 Williams-Beuren syndrome cases rules out coding variation as a major contributor to remaining variance in social behavior.
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DOI：
10.1002/mgg3.429
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发表时间：
2018-09
影响因子：
2
通讯作者：
Kozel BA
中科院分区：
文献类型：
--
作者：
Kopp ND;Parrish PCR;Lugo M;Dougherty JD;Kozel BA
染色体 7q11.23 上的大量多基因缺失会导致一系列高度渗透的身体和行为症状，称为威廉姆斯-博伊伦综合征 (WS)。特别令人感兴趣的是不寻常的社会认知特征，表现为社会认知和沟通缺陷，让人想起自闭症谱系障碍（ASD），但与正常甚至相对增强的社会动机并列。有趣的是，同一区域的重复也会导致类似 ASD 的表型以及社交恐惧症。因此，该区域明确调节人类的社会动机和行为，但相关基因尚未明确确定。在这里，我们对 85 名 WS 个体进行了深入的表型分析，并使用外显子组测序来分析常见和罕见的变异，以了解其与社会行为中剩余变异（通过社会反应量表评估）的关联。我们在这个新的患者集合中复制了之前报道的不寻常的行为症状并置，但在对威廉姆斯综合征关键区域中剩余基因拷贝的针对性分析中，我们没有发现任何具有大影响的新等位基因。然而，我们报告了两个基因中两个名义上显着的 SNP，这两个基因与威廉姆斯综合征的认知和社会表型有关，即 BAZ1B 和 GTF2IRD1。二次发现驱动的探索侧重于已知的自闭症谱系障碍基因和外显子组广泛扫描，并没有突出任何大效应的变异。对 85 名 WS 患者的全外显子组测序并不支持以下假设：在威廉姆斯综合征的剩余关键区域内存在影响社会表型的大效应变异。这种具有明确突变的深度表型和基因型患者队列为关注非编码变异和/或其他表型域的类似分析提供了机会。
Large, multigenic deletions at chromosome 7q11.23 result in a highly penetrant constellation of physical and behavioral symptoms known as Williams–Beuren syndrome (WS). Of particular interest is the unusual social‐cognitive profile evidenced by deficits in social cognition and communication reminiscent of autism spectrum disorders (ASD) that are juxtaposed with normal or even relatively enhanced social motivation. Interestingly, duplications in the same region also result in ASD‐like phenotypes as well as social phobias. Thus, the region clearly regulates human social motivation and behavior, yet the relevant gene(s) have not been definitively identified. Here, we deeply phenotyped 85 individuals with WS and used exome sequencing to analyze common and rare variation for association with the remaining variance in social behavior as assessed by the Social Responsiveness Scale. We replicated the previously reported unusual juxtaposition of behavioral symptoms in this new patient collection, but we did not find any new alleles of large effect in the targeted analysis of the remaining copy of genes in the Williams syndrome critical region. However, we report on two nominally significant SNPs in two genes that have been implicated in the cognitive and social phenotypes of Williams syndrome, BAZ1B and GTF2IRD1. Secondary discovery driven explorations focusing on known ASD genes and an exome wide scan do not highlight any variants of a large effect. Whole exome sequencing of 85 individuals with WS did not support the hypothesis that there are variants of large effect within the remaining Williams syndrome critical region that contribute to the social phenotype. This deeply phenotyped and genotyped patient cohort with a defined mutation provides the opportunity for similar analyses focusing on noncoding variation and/or other phenotypic domains.
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影响因子：
6.2
作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
通讯作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
DOI：
10.1093/bioinformatics/btu848
发表时间：
2015-05-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Euesden J;Lewis CM;O'Reilly PF
通讯作者：
O'Reilly PF
影响因子：
3.7
作者：
Gao MC;Bellugi U;Dai L;Mills DL;Sobel EM;Lange K;Korenberg JR
通讯作者：
Korenberg JR
影响因子：
3.9
作者：
Constantino, JN;Davis, SA;Reich, W
通讯作者：
Reich, W
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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