De novo large genomic deletions involving POU3F4 in incomplete partition type III inner ear anomaly in East Asian populations and implications for genetic counseling

Objective: The aim of this study was to understand the prevalence and molecular genetic etiology of incomplete partition type III (IP type III) anomaly in Koreans. We also attempted to verify the prevalence of genomic deletions in the DFNX2 locus and to look for association between inheritance patterns and mutation type in East Asian IP type III subjects.

Study Design: Retrospective case review. Setting: Tertiary referral center.

Patients: Subjects with IP type III anomaly and their biological mothers. Interventions: Sanger sequencing, array-comparative genomic hybridization (aCGH), and PCR were performed. We also analyzed the type and inheritance of the causative genetic abnormality in East Asian DFNX2 patients. Main Outcome Measure: Mutation type and occurrence.

Results: We identified IP type III in 10 (4.8%) of 206 patients with an inner ear abnormality. We confirmed an etiologic homogeneity, DFNX2, of the IP type III in this Korean population. Two (20%) of the 10 DFNX2 carried a large genomic deletion affecting POU3F4, as proved by aCGH. PCR confirmed that the 2 deletions occurred de novo. Genetic alteration occurred de novo in 29.4% (5/17) of all reported Korean IP type III cases. From this study and literature review, we observed a striking difference of de novo occurrence rate (75% versus 12.5%, p = 0.032) between large genomic deletions and point mutations in East Asian population. Conclusions: Our data suggest that different POU3F4 mutations might show different recurrence rate in siblings of the IP type III families, especially in East Asian population. Genetic counseling should be provided accordingly.