Variability in gene expression is associated with incomplete penetrance in inherited eye disorders

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 HGMD 2019.1 and cross-checked with the gnomAD 2.1 control-only dataset. Genes for which >1 variant was 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, GTEx and EyeGEx. 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 a 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.