Auditory genotype-phenotype correlation of patients with variants in STRC

Abstract

Pathogenic variants in the STRC gene are among the most common causes of autosomal recessive non-syndromic hearing loss, particularly in cases with mild-to-moderate sensorineural hearing loss (SNHL). Despite its prevalence, the clinical phenotype and natural history of STRC-related SNHL remain undercharacterized due to diagnostic challenges posed by a highly homologous pseudogene, pSTRC. This study included 23 families enrolled in the Yonsei University Hearing Loss cohort. Genetic testing was performed using either targeted deafness gene panels or whole-exome sequencing, followed by multiplex ligation-dependent probe amplification and confirmatory Sanger sequencing. A total of 23 patients with STRC-related SNHL were identified, including 12 with homozygous STRC/CATSPER2 gene deletions and 11 with other combinations of pathogenic variants. Most patients exhibited mild-to-moderate SNHL with flat or gently sloping audiometric configurations, predominantly affecting mid-to-high frequencies. No significant differences in mean PTA thresholds were observed between the two genotypic groups. Longitudinal analysis over a follow-up period of up to 4 years demonstrated stable hearing thresholds in 75% of ears, with no significant progression detected using linear mixed model analysis. Linear regression showed no age-dependent threshold shift in either ear across all genotypic subgroups. In conclusion, STRC-related hearing loss is typically mild-to-moderate, stable over time, and audiometrically similar regardless of genotypic subclassification. Given its subtle phenotype and diagnostic complexity, STRC mutations may be underrecognized without targeted screening. Incorporating STRC-specific MLPA assay into routine genetic diagnostics in patients with mild-to-moderate hearing loss may improve early detection and guide timely precision intervention.