A Novel Missense WFS1 Variant: Expanding the Mutational Spectrum Associated with Nonsyndromic Low-Frequency Sensorineural Hearing Loss

Ma, Jingyu; Wang, Rongrong; Zhang, Li; Wang, Shanshan; Tong, Shuqing; Bai, Xiaohui; Lu, Zhiming

doi:10.1155/2022/5068869

Cited by 3 publications

(1 citation statement)

References 44 publications

(37 reference statements)

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“…The WFS1 gene encodes “Wolframin”, a transmembrane protein located in the endoplasmic reticulum and ubiquitously expressed [ 191 ]. DFNA6/14/38 was largely described in the United States of America [ 192 , 193 , 194 , 195 , 196 , 197 ], Japan [ 198 , 199 , 200 , 201 , 202 , 203 ], and China [ 133 , 182 , 204 , 205 , 206 , 207 , 208 , 209 , 210 ]. In Europe, DFNA6/14/38 was reported in Dutch [ 191 , 211 , 212 , 213 ], Swiss [ 214 ], Danish [ 215 ], Hungarian [ 216 ], Finnish [ 217 ], and German [ 218 ] families.…”

Section: Autosomal Dominant Non-syndromic Hearing Loss (Dfna)mentioning

confidence: 99%

Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review

et al. 2023

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Autosomal dominant non-syndromic hearing loss (HL) typically occurs when only one dominant allele within the disease gene is sufficient to express the phenotype. Therefore, most patients diagnosed with autosomal dominant non-syndromic HL have a hearing-impaired parent, although de novo mutations should be considered in all cases of negative family history. To date, more than 50 genes and 80 loci have been identified for autosomal dominant non-syndromic HL. DFNA22 (MYO6 gene), DFNA8/12 (TECTA gene), DFNA20/26 (ACTG1 gene), DFNA6/14/38 (WFS1 gene), DFNA15 (POU4F3 gene), DFNA2A (KCNQ4 gene), and DFNA10 (EYA4 gene) are some of the most common forms of autosomal dominant non-syndromic HL. The characteristics of autosomal dominant non-syndromic HL are heterogenous. However, in most cases, HL tends to be bilateral, post-lingual in onset (childhood to early adulthood), high-frequency (sloping audiometric configuration), progressive, and variable in severity (mild to profound degree). DFNA1 (DIAPH1 gene) and DFNA6/14/38 (WFS1 gene) are the most common forms of autosomal dominant non-syndromic HL affecting low frequencies, while DFNA16 (unknown gene) is characterized by fluctuating HL. A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants.

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Section: Autosomal Dominant Non-syndromic Hearing Loss (Dfna)mentioning

confidence: 99%

Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review

et al. 2023

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Genetic resonance: dissecting the heritability and genetic correlations of human hearing acuity

Duran,

Watkins,

Neklason

et al. 2024

G3: Genes, Genomes, Genetics

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This study presents a frequency-specific, pedigree-based assessment of hearing acuity heritability. We analyzed 34 Utah Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees comprising 464 individuals, using whole-genome sequencing (WGS) and audiometric evaluations. Our analysis reveals a general decline in narrow-sense heritability as frequency increases. When calculated using the Sequential Oligogenic Linkage Analysis Routines (SOLAR) software package, narrow-sense heritability estimates drop from 51% at 250Hz to 30% at 8000Hz. Genetic correlations (Rho(G)), the degree to which genetic variation in one trait correlates with another, are higher for hearing acuity at similar frequencies. For example, Rho(G) between 250Hz and 500Hz is 0.80, and Rho(G) between 6000Hz and 8000Hz is 0.91. In contrast, frequencies distant from each other exhibit decreased Rho(G) with a genetic correlation of only 0.21 for hearing acuity at frequencies 250Hz and 8000Hz. This assessment of the genetics underlying hearing acuity in a family-based design provides new details of genetic factors influencing hearing acuity in a frequency-specific approach.

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Genotype and Phenotype Analyses of a Novel WFS1 Variant (c.2512C>T p.(Pro838Ser)) Associated with DFNA6/14/38

Velde

Huizenga

Haer‐Wigman

et al. 2023

Genes

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The aim of this study is to contribute to a better description of the genotypic and phenotypic spectrum of DFNA6/14/38 and aid in counseling future patients identified with this variant. Therefore, we describe the genotype and phenotype in a large Dutch–German family (W21-1472) with autosomal dominant non-syndromic, low-frequency sensorineural hearing loss (LFSNHL). Exome sequencing and targeted analysis of a hearing impairment gene panel were used to genetically screen the proband. Co-segregation of the identified variant with hearing loss was assessed by Sanger sequencing. The phenotypic evaluation consisted of anamnesis, clinical questionnaires, physical examination and examination of audiovestibular function. A novel likely pathogenic WFS1 variant (NM_006005.3:c.2512C>T p.(Pro838Ser)) was identified in the proband and found to co-segregate with LFSNHL, characteristic of DFNA6/14/38, in this family. The self-reported age of onset of hearing loss (HL) ranged from congenital to 50 years of age. In the young subjects, HL was demonstrated in early childhood. At all ages, an LFSNHL (0.25–2 kHz) of about 50–60 decibel hearing level (dB HL) was observed. HL in the higher frequencies showed inter-individual variability. The dizziness handicap inventory (DHI) was completed by eight affected subjects and indicated a moderate handicap in two of them (aged 77 and 70). Vestibular examinations (n = 4) showed abnormalities, particularly in otolith function. In conclusion, we identified a novel WFS1 variant that co-segregates with DFNA6/14/38 in this family. We found indications of mild vestibular dysfunction, although it is uncertain whether this is related to the identified WFS1 variant or is an incidental finding. We would like to emphasize that conventional neonatal hearing screening programs are not sensitive to HL in DFNA6/14/38 patients, because high-frequency hearing thresholds are initially preserved. Therefore, we suggest screening newborns in DFNA6/14/38 families with more frequency-specific methods.

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A Novel Missense WFS1 Variant: Expanding the Mutational Spectrum Associated with Nonsyndromic Low-Frequency Sensorineural Hearing Loss

Cited by 3 publications

References 44 publications

Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review

Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review

Genetic resonance: dissecting the heritability and genetic correlations of human hearing acuity

Genotype and Phenotype Analyses of a Novel WFS1 Variant (c.2512C>T p.(Pro838Ser)) Associated with DFNA6/14/38

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