Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/134886
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Type: | Journal article |
Title: | Different types of disease-causing non-coding variants revealed by genomic and gene expression analyses in families with X-linked intellectual disability |
Author: | Field, M.J. Sharma, R. Hackett, A. Kayumi, S. Shoubridge, C. Ewans, L.J. Ivancevic, A.M. Dudding-Byth, T. Carroll, R. Kroes, T. Gardner, A.E. Sullivan, P. Ha, T.T. Schwartz, C.E. Cowley, M.J. Dinger, M.E. Palmer, E.E. Christie, L. Shaw, M. Roscioli, T. et al. |
Citation: | Human Mutation, 2021; 42(7):835-847 |
Publisher: | Wiley |
Issue Date: | 2021 |
ISSN: | 1059-7794 1098-1004 |
Statement of Responsibility: | Michael J. Field, Raman Kumar, Anna Hackett, Sayaka Kayumi, Cheryl A. Shoubridge, Lisa J. Ewans, Atma M. Ivancevic, Tracy Dudding, Byth, Renée Carroll, Thessa Kroes, Alison E. Gardner, Patricia Sullivan, Thuong T. Ha, Charles E. Schwartz, Mark J. Cowley, Marcel E. Dinger, Elizabeth E. Palmer, Louise Christie, Marie Shaw, Tony Roscioli, Jozef Gecz, Mark A. Corbett |
Abstract: | The pioneering discovery research of X-linked intellectual disability (XLID) genes has benefitted thousands of individuals worldwide however, approximately 30% of XLID families still remain unresolved. We postulated that non-coding variants that affect gene regulation or splicing may account for the lack of a genetic diagnosis in some cases. Detecting pathogenic, gene-regulatory variants with the same sensitivity and specificity as structural and coding variants is a major challenge for Mendelian disorders. Here, we describe three pedigrees with suggestive XLID where distinctive phenotypes associated with known genes guided the identification of three different non-coding variants. We used comprehensive structural, single nucleotide and repeat expansion analyses of genome sequencing. RNA-Seq from patient-derived cell lines, RT-PCRs, western blots and reporter gene assays were used to confirm the functional effect of three fundamentally different classes of pathogenic non-coding variants: a retrotransposon insertion, a novel intronic splice donor and a canonical splice variant of an untranslated exon. In one family, we excluded a rare coding variant in ARX, a known XLID gene, in favour of a regulatory non-coding variant in OFD1 that correlated with the clinical phenotype. Our results underscore the value of genomic research on unresolved XLID families to aid novel, pathogenic non-coding variant discovery. |
Keywords: | gene regulation intellectual disability non-coding RNA-Seq splicing transcriptome whole genome sequencing X-linked |
Rights: | © 2021 Wiley Periodicals LLC |
DOI: | 10.1002/humu.24207 |
Published version: | http://dx.doi.org/10.1002/humu.24207 |
Appears in Collections: | Paediatrics publications |
Files in This Item:
File | Description | Size | Format | |
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hdl_134886.pdf | Accepted version (includes Supplementary Material & Supplementary Table2) | 5.79 MB | Adobe PDF | View/Open |
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