Abstract
Pathogenic variants in the PJVK gene cause the DFNB59 type of autosomal recessive non-syndromic hearing impairment (AR-NSHI). Phenotypes are not homogeneous, as a few subjects show auditory neuropathy spectrum disorder (ANSD), while others show cochlear hearing loss. The numbers of reported cases and pathogenic variants are still small to establish accurate genotype-phenotype correlations. We investigated a cohort of 77 Spanish familial cases of AR-NSHI, in whom DFNB1 had been excluded, and a cohort of 84 simplex cases with isolated ANSD in whom OTOF variants had been excluded. All seven exons and exon-intron boundaries of the PJVK gene were sequenced. We report three novel DFNB59 cases, one from the AR-NSHI cohort and two from the ANSD cohort, with stable, severe to profound NSHI. Two of the subjects received unilateral cochlear implantation, with apparent good outcomes. Our study expands the spectrum of PJVK mutations, as we report four novel pathogenic variants: p.Leu224Arg, p.His294Ilefs*43, p.His294Asp and p.Phe317Serfs*20. We review the reported cases of DFNB59, summarize the clinical features of this rare subtype of AR-NSHI and discuss the involvement of PJVK in ANSD.
Highlights
Inherited hearing impairment is clinically and genetically very heterogeneous
We investigated a cohort of 77 Spanish familial cases of autosomal recessive nonsyndromic hearing loss, with at least two affected siblings, in whom DFNB1 pathogenic variants had been previously excluded
We found likely causative variants in two unrelated subjects, who had no siblings with normal hearing
Summary
Inherited hearing impairment is clinically and genetically very heterogeneous. Hearing loss can be an isolated condition (non-syndromic hearing impairment, NSHI) or it can be part of the clinical signs that are characteristic of specific genetic syndromes [1]. For most of the known genes, few affected subjects have been reported to carry causative variants, and this poor knowledge of the mutational spectra is hindering the investigation of genotype-phenotype correlations in the different genetic types of NSHI [3]. The DFNB59 type of autosomal recessive (AR) NSHI (MIM #610220) is caused by pathogenic variants in the PJVK gene (MIM #610219) [4], which is located on 2q31.2, spanning 9950 bp of genomic sequence. It contains seven exons and codes for pejvakin, a 352-residue protein that belongs to the gasdermin family. Pejvakin has been reported to be associated with peroxisomes, where it would mediate their autophagic degradation (pexophagy) as a protective mechanism against the oxidative stress that is caused by noise overexposure [8,9]
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