Clinical characterization of genetic hearing loss caused by a mutation in the POU4F3 transcription factor

Objectives: To describe the detailed auditory phenotype of DFNA15, generic hearing loss associated with a mutation in the POU4F3 transcription factor, and to define genotype-phenotype correlations, namely, how specific mutati ons lead to particular clinical consequences. Design: An analysis of clinical features of hearing-impaired members of an Israeli family, family H, with autosomal dominant-inherited hearing loss. Setting: Department of Human Genetics and Molecular Medicine, Sackler Schoo l of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Audiolo gy, Rabin Medical Center, Petah Tiqwa, Israel; and audiological centers. Participants: Clinical features of 11 affected and 5 unaffected individuals older than 40 years from family H were studied. Mutation analysis was perf ormed in 6 presymptomatic individuals younger than 30 years; clinical featu res were analyzed in 4 of these family H members. Interventions: Hearing was measured by pure-tone audiometry and speech audi ometry on all participating relatives of family H. Immittance testing (tymp anometry and acoustic reflexes), auditory brainstem response, and otoacoust ic emissions were done in a selected patient population. Results: The patients presented with progressive high-tone sensorineural he aring impairment, which became apparent between ages 18 and 30 years. The h earing impairment became more severe with time, eventually causing signific ant hearing loss across the spectrum at all frequencies. Conclusions: Our results indicate that POU4F3 mutation-associated deafness cannot be identified through clinical evaluation, but only through molecula r analysis. Intrafamilial variability suggests that other genetic or enviro nmental factors may modify the age at onset and rate of progression.