The emerging global picture from our findings is an intricate and complex portrait of the genomic landscape and mutational signature of deafness-associated genes. Although this work lays the foundation for improved variant interpretation, which greatly enhances clinical decision making, significant challenges remain. For example, of coding variants with a MAF < 0.5%, missense variants predominate. They constitute 70% of all VUSs and their accurate reclassification will require better computational tools (Figure 7). The non-coding pathogenic landscape also must be defined, warranting coordinated studies to integrate expression and genomic data.
Figure 7 The Challenge of VUSs
Variant architecture correlating variant type (inner ring) and clinical significance (outer ring) for variants with MAF less than 0.5% and located within the clinically relevant regions. Of all coding variants with MAF < 0.5%, missense variants represent the majority at 61.5%; of these missense variants, 70% are classified as VUSs. Abbreviations: Indel-In, in-frame indel; Indel-Fs, frameshift indel; Mit-Mir, mitochondrial and microRNA.