Most Genetic Variants in Deafness-Associated Genes Are Missense and Rare
Having built a comprehensive resource that collates and annotates all variants in hearing loss genes and provides a clinical interpretation, we sought to explore the genomic and mutational landscape of deafness-associated genes. Our first objective was to evaluate the distribution of variants with respect to their MAF and type. Of all variants in the DVD, novel, ultra-rare (0% < MAF ≤ 0.05%), and rare (0.05% < MAF < 0.5%) variants represented 36%, 11%, and 35%, respectively (Figure 3A). When only clinically relevant variants within coding and splice-site regions were considered, the general tendency did not change. Variants with MAF < 0.5% remained the most prevalent (96%) although the distribution within this set changed, with ultra-rare variants (0% < MAF ≤ 0.05%) now representing the major category (59%) (Figure 3B). The finding that variants with a MAF < 0.5% (the threshold above which a variant is too common to be deafness causing16) account for 96% of all the variants falling within coding and splice-site regions implies that only 4% of variants can be excluded as deafness causing on the basis of MAF filtering.
Figure 3 Distribution of Variants by Location, MAF, and Type
(A and B) MAF (all variants in DVD including intronic) (A) and only variants in gene coding regions (B). Most coding variants (96%) in deafness-associated genes are novel or rare (MAF < 0.5%).
(C) Distribution of variant by their gene location.
(D) Coding variant breakdown by type showing that missense variants constitute the major set of all coding variants.
Abbreviations: FS, frameshift; SS, splice-site; inF, in-frame.
Of all variants within deafness-associated genes, ∼12% were located in the coding regions and canonical splice sites (Figure 3C). Missense variants represent the major set of all coding variants at 62%. The second most common type are synonymous variants (28%) followed by indels (4% frameshift and 2% inframe), nonsense (2%), canonical splice-site (2%), and start/stop loss (<1%) (Figure 3D).