ABSTRACT
OBJECTIVE This study aimed at identifying inner ear malformation underlying molecular determinant(s) using a large five-generation Chinese family with multiple familial cases. METHODS Model-based genetic linkage analyses were performed with the use of microsatellite polymorphisms to determine the disease locus. Mutation screening was performed with the family and unrelated population-based controls to establish molecular evidence that caused the specific X-linked inheritance pattern in the family. RESULTS Clinical investigations of the pedigree demonstrated the extremely high penetrance in the male members, but no penetrance in the female members. Linkage analyses mapped the disease to the chromosomal region Xq13.1-Xq23 (maximum X-linkage LOD score = 3.27). Mutation screening of the candidate genes in the linkage region by direct sequencing revealed a de novo missense substitution (925T→C) in the well-known deaf gene POU3F4. Direct sequencing on 110 unrelated controls did not detect any mutation. CONCLUSION a novel mutation of POU3F4 gene was identified to be the causative reason for the hearing loss in family with inner ear malformation.