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Open AccessArticle

Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders

1
Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester M13 9PT, UK
2
Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK
3
Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK
*
Author to whom correspondence should be addressed.
Genes 2020, 11(2), 179; https://doi.org/10.3390/genes11020179
Received: 30 December 2019 / Revised: 29 January 2020 / Accepted: 6 February 2020 / Published: 9 February 2020
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
Inherited eye disorders (IED) are a heterogeneous group of Mendelian conditions that are associated with visual impairment. Although these disorders often exhibit incomplete penetrance and variable expressivity, the scale and mechanisms of these phenomena remain largely unknown. Here, we utilize publicly-available genomic and transcriptomic datasets to gain insights into variable penetrance in IED. Variants in a curated set of 340 IED-implicated genes were extracted from the Human Gene Mutation Database (HGMD) 2019.1 and cross-checked with the Genome Aggregation Database (gnomAD) 2.1 control-only dataset. Genes for which >1 variants were encountered in both HGMD and gnomAD were considered to be associated with variable penetrance (n = 56). Variability in gene expression levels was then estimated for the subset of these genes that was found to be adequately expressed in two relevant resources: the Genotype-Tissue Expression (GTEx) and Eye Genotype Expression (EyeGEx) datasets. We found that genes suspected to be associated with variable penetrance tended to have significantly more variability in gene expression levels in the general population (p = 0.0000015); this finding was consistent across tissue types. The results of this study point to the possible influence of cis and/or trans-acting elements on the expressivity of variants causing Mendelian disorders. They also highlight the potential utility of quantifying gene expression as part of the investigation of families showing evidence of variable penetrance. View Full-Text
Keywords: inherited eye disease; inherited retinal disease; variable expressivity; incomplete penetrance inherited eye disease; inherited retinal disease; variable expressivity; incomplete penetrance
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Green, D.J.; Sallah, S.R.; Ellingford, J.M.; Lovell, S.C.; Sergouniotis, P.I. Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders. Genes 2020, 11, 179.

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