Abstract
Autosomal dominant non-syndromic hearing loss (ADNSHL) is genetically heterogeneous with more than 35 genes identified to date. Using a massively parallel sequencing panel targeting 159 deafness genes, we identified a novel missense variant of POU4F3 (c.982A>G, p.Lys328Glu) which co-segregated with the deafness phenotype in a three-generation Taiwanese family with ADNSHL. This variant could be classified as a “pathogenic variant” according to the American College of Medical Genetics and Genomics guidelines. We then performed subcellular localization experiments and confirmed that p.Lys328Glu compromised transportation of POU4F3 from the cytoplasm to the nucleus. POU3F4 p.Lys328Glu was located within a bipartite nuclear localization signal (NLS), and was the first missense variant in bipartite NLS of POU4F3 validated in functional studies. These findings expanded the mutation spectrum of POU4F3 and provided insight into the pathogenesis associated with aberrant POU4F3 localization.
Highlights
Autosomal dominant non-syndromic hearing loss (ADNSHL) is a heterogeneous disease entity with more than 35 genes identified to date
Prediction of pathogenicity using seven algorithms concluded that POU4F3 p.Lys328Glu (c.982A>G) was the only candidate variant that matched the inheritance pattern
We identified a novel missense variant POU4F3 p.Lys328Glu causing ADNSHL in a Taiwanese family
Summary
Autosomal dominant non-syndromic hearing loss (ADNSHL) is a heterogeneous disease entity with more than 35 genes identified to date (http://hereditaryhearingloss.org/). By using MPS-based panels, genetic causes could be determined in >50% of cases with ADNSHL3. POU4F3 (MIM #602460) is one of the earliest deafness genes identified to cause ADNSHL DFNA15. Only 12 POU4F3 causative variants have been reported in the literature, that is, six missense variants[5,6,7,8,9,10], five frameshift deletions[4, 11,12,13,14], and a large deletion encompassing the entire gene[15, 16]. Mutations in POU4F3 might lead to late-onset bilateral progressive hearing loss with down-sloping audiometric configurations[8]
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