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

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.

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.

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.

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.