To characterize the molecular profile of variants within different classification categories, we focused on variants in coding and splice regions and grouped them by type (nonsense, splice-site, frameshift indels, start loss, stop loss, in-frame indels, missense, UTRs, intronic, synonymous) across variant classifications (P, LP, VUS, LB, B). Overall, missense variants were most prevalent in all categories (Figure 5A). For P variants, loss-of-function (LoF) variants and non-LoF were equally represented (∼50%). Of LoF variants, frameshift indels were most common (47.8%), followed by nonsense and splice-site at 27.65% and 22.27%, respectively. LP variants showed a slightly different profile with mostly missense variants at ∼70%. As expected, P variants are enriched in LoF and B variants are depleted. VUSs are enriched for missense (53.5%) and synonymous (34.1%) variants, with LoF variants representing only ∼7%. We found an enrichment of LoF variants in the P (50%) and LP (16.9%) categories, whereas they represent only 7% of VUSs and a negligible proportion of LB (0.03%) and B (0.47%) variants (Figure 5A). Missense variants are most common in the LB classification at ∼95% and represent ∼70% of the LP variants and ∼50% of P variants.
Figure 5 Genomic Landscape of Deafness-Associated Genes
(A) Variant architecture by each classification category shows a strikingly distinct distribution of variant types across the five classifications.
(B) Distribution of LoF, missense, and synonymous variants is different across genes.
(C) Most LoF variants are P/LP and some genes are highly enriched in this type of variant.
(D) The contribution of missense variants to the mutational pool of hearing loss is variable across genes. However, in most genes, the majority of missense variants are VUSs.
(E) The mutational spectrum is gene specific. Splice-site indicates variants in canonical splice sites.
Only genes with ≥14 reported deafness-associated variants are included in this figure; the remaining genes are shown in Figures S4 and S5.