Mutation Spectrum and Novel Rare Variants in a Han Chinese Hearing Loss Cohort Using a Tiered Sequencing Strategy.

BACKGROUND: Hereditary hearing loss is a genetically heterogeneous disorder posing challenges for molecular diagnosis. This study aimed to characterize the mutation spectrum, including rare and previously unreported variants, using a tiered strategy in a Han Chinese cohort from Southwest China. METHODS: In this retrospective study, 43 patients underwent targeted hotspot screening, followed by whole-exome sequencing in 11 patients with no hotspot variants detected. Variants were annotated and interpreted according to American College of Medical Genetics and Genomics guidelines. RESULTS: Initial hotspot screening established molecular diagnoses in 23 patients based on seven pathogenic or likely pathogenic variants in MT-RNR1, GJB2, and SLC26A4. Whole-exome sequencing identified six additional rare variants in CDH23, ILDR1, OTOF, and SLC12A2, and established two diagnoses involving ILDR1 and CDH23. A previously unreported SLC12A2 missense variant, c.2936A>G (p.Glu979Gly) was identified as a variant of uncertain significance and retained as a candidate finding. CDH23 c.5311C>T (p.Arg1771Ter) has not previously been reported in Han Chinese patients with hearing loss, to our knowledge. CONCLUSIONS: These findings expand the mutation spectrum of hereditary hearing loss in a Han Chinese cohort from Southwest China and highlight the practical value of a tiered testing strategy integrating targeted hotspot screening with whole-exome sequencing.