Genotype-phenotype correlation-driven precision management in hereditary conductive and mixed hearing loss.

OBJECTIVE

To investigate genetic etiologies of conductive/mixed hearing loss (CHL/MHL) and guide management through genotype–phenotype correlations.

METHODS

Retrospective study of 98 patients (29 syndromic, 69 non-syndromic) with CHL/MHL. Clinical evaluations and next-generation sequencing were performed. Surgical outcomes and familial patterns were analyzed.

RESULTS

Syndromic cases showed high genetic confirmation (96.6%), including Branchio-Oto syndromes (BOS), Treacher Collins syndromes (TCS), Van der Hoeve syndromes (VH), and NOG-related symphalangism syndromes (NOG-SSD). Temporal bone anomalies were common in BOS (87.5%), CHARGE/Klippel-Feil syndromes (100%), and TCS (42.9%) but were absent in NOG-SSD/Townes-Brocks syndromes (TBS). Middle ear surgery improved hearing (TCS/VH: 35.63/22.50 dB HL; NOG-SSD: 25.00 dB HL). Non-syndromic cases included congenital middle ear malformations (CMEM, n = 14) with temporal bone anomalies and otosclerosis (n = 55, mostly adult onset). Genetic diagnosis was rare (1.5%, one novel EMX2 variant in CMEM). Stapedotomy achieved consistent improvements (28.25 dB HL).

CONCLUSION

Syndromic CHL/MHL has high genetic diagnostic yields and variable phenotypes, necessitating genomic testing for management. EMX2 is implicated in CMEM, while otosclerosis remains genetically unexplained. Surgical outcomes depend on etiology, with syndromic cases showing heterogeneous responses versus uniform success in non-syndromic patients. Molecular diagnostics enable precise diagnosis, prognosis, and treatment optimization, advancing precision otology for CHL/MHL.