Case ReportA novel pathogenic variant c.975G>A (p.Trp325*) in the POU3F4 gene in Yakut family (Eastern Siberia, Russia) with the X-linked deafness-2 (DFNX2)
Introduction
One in 1000 newborns is affected by congenital deafness [1], [2]. About half of all cases are hereditary and inherited by a recessive autosomal pattern (70–80%) or a dominant autosomal pattern (10–20%) [3]. The proportion of X-linked deafness (DFNX) is less than 1–2% [3]. One of the common forms of X-linked deafness is the perilymphatic Gusher-deafness syndrome also known as the X-linked deafness-2 (DFNX2, MIM 304400) caused by pathogenic variants in the POU3F4 gene (MIM 300039, Xq21) [4]. DFNX2 is characterized by progressive conductive and sensorineural hearing loss and a pathognomonic temporal bone deformation that includes dilatation of the inner auditory canal and a fistulous connection between the internal auditory canal and the cochlear basal turn, resulting in a perilymphatic fluid “gusher” during stapes surgery [4], [5], [6], [7], [8]. The POU3F4 gene encodes the transcription factor POU3F4 (Brain 4). Douville et al. (1994) showed that the rat homolog of POU3F4, called RHS2, is expressed during embryonic development in the brain, the neural tube, and the otic vesicle at 15.5 and 17.5 days after conception [9]. More than 70 pathogenic variants (41 missense/nonsense substitutions, 11 small deletions, 3 small insertions, 15 large deletions, one large insertion, and 3 complex variants) have been described for the POU3F4 gene in the Human Gene Mutation Database (accessed July, 2017) [10] and 156 variants of different clinical significance in the ClinVar Database (accessed July, 2017) [11]. However, data on the clinical characteristics and the outcomes of patients with different pathogenic POU3F4 variants causing DFNX2 are scarce for populations worldwide.
In our previous studies in the Sakha Republic (Eastern Siberia, Russia), we found that hearing impairment in 192 out of 393 examined patients (48.9%) was caused by the pathogenic variants in the GJB2 gene (MIM 220290) while the causes of ∼50% of early childhood deafness cases have not been determined [12]. To identify the causes of hearing loss in GJB2-negative patients (n = 98) we performed computed tomography examinations and revealed one Yakut family (belonging to indigenous population of the Sakha Republic) with inner ear abnormalities specific to DFNX2.
In this report, we conducted comprehensive clinical examination including computed tomography, audiological examination, magnetic resonance imaging, and stabilometric examination of four members of one Yakut family (two affected half-siblings and their non-affected parents) with Х-linked recessive deafness associated with novel variant c.975G>A (p.Trp325*) in the POU3F4 gene.
Section snippets
Computed tomography (CT)
CT-imaging of the temporal bone was performed using the 4-slice Siemens SOMATOM Sensation 4 CT scanner (Germany). The section thickness of the axial plane was set to 1 mm (InnerEarSpi software). The 2D images in native axial planes were used for the visualization of temporal bone structure.
Audiological examination (AE)
Pure tone audiometry was performed using the audiometer MAICO ST 20 (Germany) at air conduction frequencies 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 kHz and at bone conduction frequencies 0.25, 0.5, 1.0, 4.0 kHz with
Case report
We revealed identical abnormalities of the inner ear in two half-brothers with DFNX2 (MIM 304400) from one Yakut family belonging to indigenous population of the Sakha Republic (Fig. 1). We observed this family during two years 2012–2014 (the ages of both brothers at examinations were 9–10 years and 11–12 years, respectively). Both brothers are the students of special boarding school for deaf children. They had a prelingual hearing loss, normal intelligence, normal physical development and no
Discussion
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 (Appendix B. Supplementary Fig. 3). Transition c.975G>A in the POU3F4 gene had not previously
Conclusion
Novel hemizygous transition c.975G>A (p.Trp325*) in the POU3F4 gene was revealed in two deaf half-brothers from one Yakut family (Eastern Siberia, Russia) with identical inner ear abnormalities specific to X-linked deafness-2 (DFNX2). The data from comprehensive clinical evaluation (computed tomography, audiological examination, magnetic resonance imaging and stabilometric examination) of four members of this family expand clinical information both for the DFNX2-affected males and for the
Competing interests
All authors declare that they have no competing interests.
Acknowledgments
We thank all patients and blood sample donors who have contributed to this study. Special thanks to Vincent Zvénigorosky (Institut de Médecine Légale, Université de Strasbourg, Strasbourg, France) for valuable corrections to the manuscript.
This work was supported by the grants of the Russian Foundation for Basic Research (#16-34-00564_mol_a, #16-34-00234_mol_a, #17-29-06016_ofi_m), by the Project of the Ministry of Education and Science of the Russian Federation (#6.1766.2017), by a Second
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These authors contributed equally to this work.