Genome-wide investigation of an ID cohort reveals de novo 3'UTR variants affecting gene expression
Abstract
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.
Citation
Devanna , P , van de Vorst , M , Pfundt , R , Gilissen , C & Vernes , S C 2018 , ' Genome-wide investigation of an ID cohort reveals de novo 3'UTR variants affecting gene expression ' , Human Genetics , vol. 137 , no. 9 , pp. 717-721 . https://doi.org/10.1007/s00439-018-1925-9
Publication
Human Genetics
Status
Peer reviewed
ISSN
0340-6717Type
Journal article
Rights
Copyright © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Description
Open access funding provided by Max Planck Society. This work was funded by a Marie Curie Career Integration Grant (PCIG12-GA-2012-333978) and a Max Planck Research Group Grant, both awarded to S.C.V.Collections
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