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

Abstract

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.

The mutation spectrum in familial versus sporadic congenital cataract based on next-generation sequencing

“…The phenomenon in which identified heterozygous variants are also present in unaffected parents in sporadic cases (Table 2) might be explained by incomplete and variable penetrance; the underlying mechanisms of this phenomenon remain largely unknown. A recent study also provides support showing that variants associated with inherited eye disorders are frequently encountered in unaffected individuals and that one in six genes implicated in inherited eye disorders are potentially associated with variable penetrance [52]. The number of variants and genes that do not segregate (Table 2) is relatively high in our study.…”

Next-Generation Sequencing Applications for Inherited Retinal Diseases

“…In a study by Green et al, IRD genes typically associated with incomplete inheritance significantly correlated with greater variability in levels of expression in a healthy population in several tissue types, including the eye. This implies that cis and or trans elements may be influencing variability in expression and in turn, contribute to disease states in patients [ 148 ]. This may also result in higher-than-expected allele frequencies for pathogenic variants located in these genes in “healthy” control databases, such as gnomAD [ 149 ].…”

The Impact of Modern Technologies on Molecular Diagnostic Success Rates, with a Focus on Inherited Retinal Dystrophy and Hearing Loss

“…Despite the relatively high population frequency, the pathogenicity of the p.[Ser192Tyr;Arg402Gln] allele has been suggested when present in a homozygous state or in a triallelic genotype with a known pathogenic TYR variant in trans [ 172 , 173 ]. Studies suggest that one in six genes implicated in RD is possibly associated with variable penetrance due to variability in expression levels [ 174 , 175 ]. Examples of strong evidence for variants with reduced penetrance, implicated in RD or HL, have been reported for ABCA4 [ 113 , 176 ], COCH [ 177 ], PRPF31 [ 178 ], and RIPOR2 [ 179 ].…”