Dataset Information

Excess of Rare Missense Variants in Hearing Loss Genes in Sporadic Meniere Disease.

ABSTRACT: Meniere's disease (MD) is a clinical spectrum of rare disorders characterized by vertigo attacks, associated with sensorineural hearing loss (SNHL) and tinnitus involving low to medium frequencies. Although it shows familial aggregation with incomplete phenotypic forms and variable expressivity, most cases are considered sporadic. The aim of this study was to investigate the burden for rare variation in SNHL genes in patients with sporadic MD. We conducted a targeted-sequencing study including SNHL and familial MD genes in 890 MD patients to compare the frequency of rare variants in cases using three independent public datasets as controls. Patients with sporadic MD showed a significant enrichment of missense variants in SNHL genes that was not found in the controls. The list of genes includes GJB2, USH1G, SLC26A4, ESRRB, and CLDN14. A rare synonymous variant with unknown significance was found in the MARVELD2 gene in several unrelated patients with MD. There is a burden of rare variation in certain SNHL genes in sporadic MD. Furthermore, the interaction of common and rare variants in SNHL genes may have an additive effect on MD phenotype. This study will contribute to design a gene panel for the genetic diagnosis of MD.

SUBMITTER: Gallego-Martinez A

PROVIDER: S-EPMC6385525 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Excess of Rare Missense Variants in Hearing Loss Genes in Sporadic Meniere Disease.

Gallego-Martinez Alvaro A Requena Teresa T Roman-Naranjo Pablo P Lopez-Escamez Jose A JA

Frontiers in genetics 20190215

Meniere's disease (MD) is a clinical spectrum of rare disorders characterized by vertigo attacks, associated with sensorineural hearing loss (SNHL) and tinnitus involving low to medium frequencies. Although it shows familial aggregation with incomplete phenotypic forms and variable expressivity, most cases are considered sporadic. The aim of this study was to investigate the burden for rare variation in SNHL genes in patients with sporadic MD. We conducted a targeted-sequencing study including S ...[more]

PMID: 30828346

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Project description:BackgroundHereditary hearing loss (HL) is heterogeneous in terms of their phenotypic features, modes of inheritance, and causative gene mutations. The contribution of genetic variants to sporadic HL remains largely expanding. Either recessive or de novo dominant variants could result in an apparently sporadic occurrence of HL. In an attempt to find such variants we recruited 128 Chinese patients with sporadic nonsyndromic sensorineural HL (NSHL) and performed targeted deafness multigene sequencing in these unrelated trios-families to elucidate the molecular basis.MethodsWe analyzed a total of 384 available members (probands and their two parents) from 128 unrelated Chinese families presenting with bilateral sensorineural HL, in which previous screening had found no mutations with the GJB2, SLC26A4, and MT-RNR1 genes. We used a targeted genomic enrichment platform to simultaneously capture exons, splicing sites, and immediate flanking intron sequences of 127 known deafness genes. Sanger sequencing was used to identify probands and their two parents segregating causative variants in the candidate gene.ResultsWe observed that two heterozygous de novo WFS1 mutations in exon 8: c.2051C>T (p.A684V) and c.2590G>A (p.E864K) in five families. The two de novo WFS1 mutations were found in 3.9% (5/128) of sporadic HL patients. We found that four of the five patients had the same de novo p.A684V mutation, and their audiograms showed symmetrical bilateral and profound sensorineural hearing impairments at all frequencies, but only the proband with de novo p.E864K mutation demonstrated significantly bilateral moderate low-mid frequency sensorineural HL. Our data suggest that this WFS1 p.A684V is likely to be a de novo mutational hot spot.ConclusionsWe found 3.9% (5/128) of sporadic NSHL is caused by de novo WFS1 mutations. Our data provide that the de novo p.E864K mutation is first identified and de novo p.A684V mutation is likely to be a mutational hot spot in WFS1. It is the first study to highlight that WFS1 gene with the two de novo mutations has been indicated to classify the distinct hearing impairment phenotypes. Furthermore, de novo p.A684V serves as a WFS1 mutational hot spot that was found in the Chinese population with sporadic childhood NSHL, and our study also provides pointers toward the necessity for sequencing of asymptomatic parents of a sporadic case with an apparent dominant pathogenic variant.

Dataset Information

Excess of Rare Missense Variants in Hearing Loss Genes in Sporadic Meniere Disease.

Publications

Excess of Rare Missense Variants in Hearing Loss Genes in Sporadic Meniere Disease.

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