Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory of Molecular Genetics, |
RCV000735984 | SCV000863562 | pathogenic | X-linked mixed hearing loss with perilymphatic gusher | 2017-09-10 | criteria provided, single submitter | research | We revealed a novel hemizygous transition c.975G>A in the POU3F4 gene in two deaf half-brothers from one Yakut family (Eastern Siberia, Russia) with identical inner ear abnormalities specific to the X-linked deafness-2 (DFNX2, MIM 304400). The c.975G>A transition leads to a stop codon (p.Trp325*) in the evolutionary conservative and functionally significant homeodomain of the POU3F4 (Brain 4) protein. Transition c.975G>A in the POU3F4 gene had not previously been reported in the 1000 Genomes, the ESP6500, and the ExAC projects. In our study the c.975G>A (p.Trp325*) variant was not found in other examined GJB2-negative patients with hearing loss (deaf Yakut males, n = 68) and in the control samples (healthy Yakut females, n = 123). The comprehensive clinical examination of both half-brothers revealed the association of novel truncating transition c.975G>A (p.Trp325*) in the POU3F4 gene with inner ear malformations ("corkscrew" cochlea with an absence of modiolus) and mixed (sensorineural and conductive) progressive bilateral hearing loss. These clinical features correspond to early reported cases of the male patients with hemizygous pathogenic variants in the POU3F4 gene associated with DFNX2. Moreover, the enlargement of semicircular canals and the postural disorders manifesting as a moderate vertical instability according to the Romberg test (PMID:29287890 - Appendix B. Supplementary Fig. 2C) were detected by additional MRI and computed stabilometry in two affected siblings with c.975G>A (p.Trp325*) in the POU3F4 gene. Thus, we believe that our findings expand currently available clinical information about the male patients with X-linked deafness-2 (DFNX2, MIM 304400) caused by pathogenic variants in POU3F4 gene. In addition, thorough clinical examination of mother of the probands who was heterozygous for c.975G>A (p.Trp325*) revealed some clinical features of the X-linked deafness-2: inner ear malformations (acoustic canal abnormalities with a cylindrical shape on the left side and a conic shape on the right side), different types of hearing thresholds (with the better ear up to 20 dB at low frequencies and up to 25 dB at high frequencies), the enlargements of semicircular canals, and the postural disorders manifesting as a moderate vertical instability according to the Romberg test. Similar clinical findings were observed in some cases in females heterozygous for pathogenic variants in the POU3F4 gene. |