Aim: The aim of this study was to report a novel POU Class 3 Homeobox 4 (POU3F4) variant and to provide further guidance on genetic counseling for incomplete partition (IP) type III families in the Korean population by showing two new contrasting cases in terms of genotypes and inheritance. Materials and Methods: Two consecutively recruited hearing-impaired probands with seemingly nonsyndromic features and their biological mothers were included in this study. Sanger sequencing and quantitative polymerase chain reaction (PCR) assays were performed for POU3F4. Results: A novel frameshift variant of POU3F4, c.852delC (p.Ile285Serfs*3), was identified in one of the patients. This mutation is predicted to truncate the protein within the POU homeodomain, resulting in the complete loss of the last nucleus localization signal. The proband's biological mother was also shown to be a carrier of this c.852delC (p.Ile285Serfs*3) mutant allele. A de novo genomic deletion on chromosome Xq21.2 was confirmed in another subject via quantitative PCR. This subject's biological mother, however, was not a carrier of this deletion. This indicates that the large upstream deletion of POU3F4 in the second proband occurred de novo. This finding is compatible with the previously proposed tendency for a high de novo rate of large genomic deletions involving the X-linked deafness-2 (DFNX2) locus. Conclusion: This study adds a novel, probably pathogenic POU3F4 truncation variant to the literature and provides guidance toward effective genetic counseling for IP III subjects based on more frequent de novo occurrence of POU3F4 deletions than POU3F4 point variants.
Keywords: deletion; frameshift; incomplete partition type III.