Genome-wide investigation of an ID cohort reveals de novo 3'UTR variants affecting gene expression.
Genome-wide investigation of an ID cohort reveals de novo 3'UTR variants affecting gene expression.
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DOI：
10.1007/s00439-018-1925-9
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发表时间：
2018-09
期刊：
影响因子：
5.3
通讯作者：
Vernes SC
中科院分区：
文献类型：
--
作者：
Devanna P;van de Vorst M;Pfundt R;Gilissen C;Vernes SC
智力残疾（ID）是一种严重的神经发育障碍与遗传异质性的原因。大规模测序已导致许多基因破坏突变的鉴定;然而，相当大比例的病例缺乏分子诊断。因此，仍然有很多要揭示的遗传基础的ID的一个完整的理解。基因组的非编码区中存在的遗传变异已被强调为神经发育障碍的潜在贡献者，因为它们在调节基因表达的作用。然而，非编码变体的功能表征仍然具有挑战性。我们描述了50名患者的ID队列中3 'UTR调节区从头非编码变异的鉴定和表征。该队列先前通过CNV、全外显子组和全基因组分析筛选结构和编码致病性变体。我们在这50个基因组的3′UTR区域内鉴定了44个高置信度的单核苷酸非编码变体。这些变异中有四个位于预测的miRNA结合位点内，因此假设具有调控后果。功能测试表明，其中两种变体干扰了miRNA介导的对其靶基因AMD 1和FAIM的调节。这两种变异都是在同一个人身上发现的，它们的功能后果可能指向这种变异在智力残疾中的潜在作用。本文的在线版本（10.1007/s 00439 -018-1925-9）包含补充材料，可供授权用户使用。
Intellectual disability (ID) is a severe neurodevelopmental disorder with genetically heterogeneous causes. Large-scale sequencing has led to the identification of many gene-disrupting mutations; however, a substantial proportion of cases lack a molecular diagnosis. As such, there remains much to uncover for a complete understanding of the genetic underpinnings of ID. Genetic variants present in non-coding regions of the genome have been highlighted as potential contributors to neurodevelopmental disorders given their role in regulating gene expression. Nevertheless the functional characterization of non-coding variants remains challenging. We describe the identification and characterization of de novo non-coding variation in 3′UTR regulatory regions within an ID cohort of 50 patients. This cohort was previously screened for structural and coding pathogenic variants via CNV, whole exome and whole genome analysis. We identified 44 high-confidence single nucleotide non-coding variants within the 3′UTR regions of these 50 genomes. Four of these variants were located within predicted miRNA binding sites and were thus hypothesised to have regulatory consequences. Functional testing showed that two of the variants interfered with miRNA-mediated regulation of their target genes, AMD1 and FAIM. Both these variants were found in the same individual and their functional consequences may point to a potential role for such variants in intellectual disability. The online version of this article (10.1007/s00439-018-1925-9) contains supplementary material, which is available to authorized users.
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DOI：
10.1093/bioinformatics/btq033
发表时间：
2010-03-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Quinlan AR;Hall IM
通讯作者：
Hall IM
影响因子：
11
作者：
Devanna P;Chen XS;Ho J;Gajewski D;Smith SD;Gialluisi A;Francks C;Fisher SE;Newbury DF;Vernes SC
通讯作者：
Vernes SC
影响因子：
3.7
作者：
Coccia E;Calleja-Yagüe I;Planells-Ferrer L;Sanuy B;Sanz B;López-Soriano J;Moubarak RS;Munell F;Barneda-Zahonero B;Comella JX;Pérez-García MJ
通讯作者：
Pérez-García MJ
影响因子：
168.9
作者：
Rauch, Anita;Wieczorek, Dagmar;Strom, Tim M.
通讯作者：
Strom, Tim M.
影响因子：
4.5
作者：
Hamdan FF;Srour M;Capo-Chichi JM;Daoud H;Nassif C;Patry L;Massicotte C;Ambalavanan A;Spiegelman D;Diallo O;Henrion E;Dionne-Laporte A;Fougerat A;Pshezhetsky AV;Venkateswaran S;Rouleau GA;Michaud JL
通讯作者：
Michaud JL