Deletion of and novel missense mutation in POU3F4 in 2 families segregating X-linked nonsyndromic deafness.

OBJECTIVE To analyze the physical manifestations and genetic features of 2 families segregating X-linked deafness, which is most commonly reported to be caused by mutations of the POU domain gene POU3F4 at the DFN3 locus. DESIGN Computed tomographic study of the temporal bone in probands from each family, followed by mutation screening and deletion mapping of POU3F4 in family members. SETTING Two midwestern genetics clinics. PARTICIPANTS Two families with X-linked deafness. MAIN OUTCOME MEASURES Anomalies of the inner ear in the probands; results of gene mapping and severity and effects of hearing loss in the family members. RESULTS In the first family, a large deletion was identified that includes POU3F4 and extends upstream approximately 530 kilobases; in the second family, a novel serine-to-leucine (S228L) amino acid mutation was identified in the POU-specific domain of POU3F4. Both the deletion and the missense mutation segregate with the clinical phenotype and are causally related to the deafness in these families. CONCLUSIONS Deafness related to the POU3F4 gene is associated with dilation of the internal auditory canal and a spectrum of other temporal bone anomalies that range in severity from mild to severe dysplasia of the cochlea and semicircular canals. The consequence of these anomalies is a congenital mixed hearing loss, the sensorineural component of which progresses over time. Affected males can also present with vestibular dysfunction that is associated with delayed developmental motor milestones. Intrafamilial variability occurs.