Copy number variants analysis in a cohort of isolated and syndromic developmental delay/intellectual disability reveals novel genomic disorders, position effects and candidate disease genes
Copy number variants analysis in a cohort of isolated and syndromic developmental delay/intellectual disability reveals novel genomic disorders, position effects and candidate disease genes
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DOI：
10.1111/cge.13009
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发表时间：
2017-10-01
影响因子：
3.5
通讯作者：
Ferrero, G. B.
中科院分区：
文献类型：
--
作者：
Di Gregorio, E.;Riberi, E.;Ferrero, G. B.
背景阵列比较基因组杂交（阵列-CGH）是一种广泛使用的检测与发育迟缓/智力残疾（DD/ID）相关的拷贝数变异（CNVs）的技术。和功能的信息，以评估的CNVs的致病性。结果我们确定了非良性CNVs的29%的患者。在致病性变异（11%）中，检测到的产量与文献一致，我们发现了罕见的基因组疾病和跨越已知疾病基因的CNV。我们进一步确定并讨论了51例可能致病的CNVs跨越新的候选基因，包括编码突触成分和/或参与皮质生成的蛋白质的基因。此外，我们确定了两个删除跨越潜在的拓扑相关结构域（ESTA）的边界可能会影响监管landscape.Discussion和conclusionWe显示如何阵列CGH数据的表型和遗传分析允许解开复杂的情况下，确定罕见的疾病基因，并揭示意想不到的位置效果。
BackgroundArray-comparative genomic hybridization (array-CGH) is a widely used technique to detect copy number variants (CNVs) associated with developmental delay/intellectual disability (DD/ID).AimsIdentification of genomic disorders in DD/ID.Materials and methodsWe performed a comprehensive array-CGH investigation of 1,015 consecutive cases with DD/ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs.ResultsWe identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries probably affecting the regulatory landscape.Discussion and conclusionWe show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects.