Genomic Biomarkers and Mutational Landscape of Nonsyndromic Hearing Loss (NSHL) in the Singaporean Population: Clinical Translational Implications

Nonsyndromic hearing loss (NSHL) is a highly prevalent, genetically heterogeneous condition, yet its molecular basis in the Singaporean population remains underexplored. We performed whole-exome sequencing and integrative bioinformatics analysis in 115 patients with NSHL to define population-specific genetic biomarkers. A molecular diagnosis was achieved in 57% of cases, with 76% of identified variants classified as pathogenic or likely pathogenic and 24% exhibiting high pathogenic potential. Common East Asian NSHL genes, including <i>GJB2</i>, <i>SLC26A4</i>, and <i>OTOF</i>, were frequently detected alongside less prevalent genes such as <i>ACTG1</i>, <i>CEACAM16</i>, <i>COL11A2</i>, <i>DIAPH1</i>, <i>KCQN4</i>, <i>MYH14</i>, <i>MYO6</i>, <i>MYO7A</i>, <i>MYO15A</i>, <i>SLC17A8</i>, <i>SMPX</i>, <i>STRC</i>, <i>TJP2</i>, <i>TMC1</i>, <i>TMPRSS3</i>, highlighting extensive genetic heterogeneity. Notably, multiple novel variants, including <i>MYO6</i> c.554-2A>G, and TNC p.N750Y, were identified, expanding the known mutational spectrum of <i>NSHL</i>. Genotype-phenotype correlations revealed that <i>GJB2</i> variants were primarily associated with mild to moderate hearing loss, whereas <i>SLC26A4</i> variants correlated with severe to profound phenotypes in the Singaporean populations. Collectively, our study provides important insights into the genetic architecture of NSHL in Singapore's population. In addition, it supports improved molecular diagnosis yield and informed clinical management decisions as well as the advancement of precision medicine approaches aimed at reducing the burden of hearing loss in the region.