Dataset Information

Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants.

ABSTRACT: The mutational spectrum of many genes and their contribution to the global prevalence of hereditary hearing loss is still widely unknown. In this study, we have performed the mutational screening of EYA4 gene by DHLPC and NGS in a large cohort of 531 unrelated Spanish probands and one Australian family with autosomal dominant non-syndromic hearing loss (ADNSHL). In total, 9 novel EYA4 variants have been identified, 3 in the EYA4 variable region (c.160G?>?T; p.Glu54*, c.781del; p.Thr261Argfs*34 and c.1078C?>?A; p.Pro360Thr) and 6 in the EYA-HR domain (c.1107G?>?T; p.Glu369Asp, c.1122G?>?T; p.Trp374Cys, c.1281G?>?A; p.Glu427Glu, c.1282-1G?>?A, c.1601C?>?G; p.S534* and an heterozygous copy number loss encompassing exons 15 to 17). The contribution of EYA4 mutations to ADNSHL in Spain is, therefore, very limited (~1.5%, 8/531). The pathophysiology of some of these novel variants has been explored. Transient expression of the c-myc-tagged EYA4 mutants in mammalian COS7 cells revealed absence of expression of the p.S534* mutant, consistent with a model of haploinsufficiency reported for all previously described EYA4 truncating mutations. However, normal expression pattern and translocation to the nucleus were observed for the p.Glu369Asp mutant in presence of SIX1. Complementary in silico analysis suggested that c.1107G?>?T (p.Glu369Asp), c.1281G?>?A (p.Glu427Glu) and c.1282-1G?>?A variants alter normal splicing. Minigene assays in NIH3T3 cells further confirmed that all 3 variants caused exon skipping resulting in frameshifts that lead to premature stop codons. Our study reports the first likely pathogenic synonymous variant linked to DFNA10 and provide further evidence for haploinsufficiency as the common underlying disease-causing mechanism for DFNA10-related hearing loss.

SUBMITTER: Morin M

PROVIDER: S-EPMC7148344 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants.

Morín Matias M Borreguero Lucía L Booth Kevin T KT Lachgar María M Huygen Patrick P Villamar Manuela M Mayo Fernando F Barrio Luis Carlos LC Santos Serrão de Castro Luciana L Morales Carmelo C Del Castillo Ignacio I Arellano Beatriz B Tellería Dolores D Smith Richard J H RJH Azaiez Hela H Moreno Pelayo M A MA

Scientific reports 20200410 1

The mutational spectrum of many genes and their contribution to the global prevalence of hereditary hearing loss is still widely unknown. In this study, we have performed the mutational screening of EYA4 gene by DHLPC and NGS in a large cohort of 531 unrelated Spanish probands and one Australian family with autosomal dominant non-syndromic hearing loss (ADNSHL). In total, 9 novel EYA4 variants have been identified, 3 in the EYA4 variable region (c.160G > T; p.Glu54*, c.781del; p.Thr261Argfs*34 a ...[more]

PMID: 32277154

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Project description:A variant in a transcription factor gene, POU4F3, is responsible for autosomal dominant nonsyndromic hereditary hearing loss, DFNA15. To date, 14 variants, including a whole deletion of POU4F3, have been reported to cause HL in various ethnic groups. In the present study, genetic screening for POU4F3 variants was carried out for a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA15 in the Japanese population. Massively parallel DNA sequencing of 68 target candidate genes was utilized in 2,549 unrelated Japanese HL patients (probands) to identify genomic variations responsible for HL. The detailed clinical features in patients with POU4F3 variants were collected from medical charts and analyzed. Novel 12 POU4F3 likely pathogenic variants (six missense variants, three frameshift variants, and three nonsense variants) were successfully identified in 15 probands (2.5%) among 602 families exhibiting autosomal dominant HL, whereas no variants were detected in the other 1,947 probands with autosomal recessive or inheritance pattern unknown HL. To obtain the audiovestibular configuration of the patients harboring POU4F3 variants, we collected audiograms and vestibular symptoms of the probands and their affected family members. Audiovestibular phenotypes in a total of 24 individuals from the 15 families possessing variants were characterized by progressive HL, with a large variation in the onset age and severity with or without vestibular symptoms observed. Pure-tone audiograms indicated the most prevalent configuration as mid-frequency HL type followed by high-frequency HL type, with asymmetry observed in approximately 20% of affected individuals. Analysis of the relationship between age and pure-tone average suggested that individuals with truncating variants showed earlier onset and slower progression of HL than did those with non-truncating variants. The present study showed that variants in POU4F3 were a common cause of autosomal dominant HL.

Dataset Information

Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants.

Publications

Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants.

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