Genetic identification and molecular modeling characterization of a novel POU3F4 variant in two Italian deaf brothers

In this report, we describe a novel, probably pathogenic hemizygous variant c.870G > T (p.Lys290Asn) in the POU3F4 gene in two deaf brothers from one Italian family with identical inner ear abnormalities specific to X-linked deafness-2 (DFNX2). In addition, we performed homology modeling to predict the effect of the missense variant on the protein structure showing a possible disruption of the normal folding. The identification of pathogenic variants causing X-linked recessive deafness will improve molecular diagnosis, genetic counseling, and knowledge of the molecular epidemiology of hearing loss among Italian individuals. Taken together, we recommend preoperative gene mutation analysis in patients who have DFNX2 diagnosed on the basis of characteristic radiological findings, in order to provide with better prognostic information, the risk of recurrence, and improved rehabilitation options. Finally, the present work strengthens the hypothesis that DFNX-2 could be considered as a syndromic deafness, since mixed hearing loss is associated with other dysfunctions of the neuropsychological profile of the patients.