Evaluation of autosomal dominant retinal dystrophy genes in an unaffected cohort suggests rare or private missense variants may often be benign

Abstract

Background: Many genes have been reported as harboring autosomal dominant mutations causing retinal dystrophy. As newly available gene panel sequencing and whole exome sequencing will open these genes up to greater scrutiny, we assess the rate of rare coding variation in these genes among unaffected individuals to provide context for variants that will be discovered when clinical subjects are sequenced.

Methods: Publicly available data from the Exome Variant Project were analyzed, focusing on 36 genes known to harbor mutations causing autosomal dominant macular dystrophy.

Results: Rates of rare (minor allele frequency ≤0.1%) and private missense variants within autosomal dominant retinal dystrophy genes were found to occur at a high frequency in unaffected individuals, while nonsense variants were not.

Conclusions: We conclude that rare missense variations in most of these genes identified in individuals with retinal dystrophy cannot be confidently classified as disease-causing in the absence of additional information such as linkage or functional validation.

Figure 1

Rare Variant Identification is Correlated With Coding Sequence Length. Coding sequence (CDS) length in nucleotides is plotted against the proportion of individuals carrying a very rare (MAF <0.1%) missense variant. A very strong positive correlation is observed (Pearson’s correlation coefficient r = 0.89), indicating that genes with long coding sequences are more likely to have a high rate of rare missense variants independent of the functional impact of those variants.