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

Abstract

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.

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

“…Autosomal dominant non-syndromic sensorineural deafness 6/14/38 (DFNA6/14/38) is caused by heterozygous mutations in the WFS1 gene on chromosome 4p16 [ 11 ]. The DFNA6, DFNA14, and DFNA38 loci were initially described separately but were later found to be associated with pathogenic variants in the same gene ( WFS1 ) [ 191 ]. Mutations in the WSF1 gene can be responsible for both autosomal dominant non-syndromic HL (DFNA6/14/38) and Wolfram syndrome (an autosomal recessive disorder characterized by diabetes mellitus, diabetes insipidus, optic atrophy, and high-frequency sensorineural HL) [ 11 , 191 ].…”

“…The DFNA6, DFNA14, and DFNA38 loci were initially described separately but were later found to be associated with pathogenic variants in the same gene ( WFS1 ) [ 191 ]. Mutations in the WSF1 gene can be responsible for both autosomal dominant non-syndromic HL (DFNA6/14/38) and Wolfram syndrome (an autosomal recessive disorder characterized by diabetes mellitus, diabetes insipidus, optic atrophy, and high-frequency sensorineural HL) [ 11 , 191 ]. The WFS1 gene encodes “Wolframin”, a transmembrane protein located in the endoplasmic reticulum and ubiquitously expressed [ 191 ].…”

“…Mutations in the WSF1 gene can be responsible for both autosomal dominant non-syndromic HL (DFNA6/14/38) and Wolfram syndrome (an autosomal recessive disorder characterized by diabetes mellitus, diabetes insipidus, optic atrophy, and high-frequency sensorineural HL) [ 11 , 191 ]. 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 ].…”

“…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. Other cases of DFNA6/14/38 were observed in Taiwan [ 219 ], the Republic of Korea [ 220 , 221 ], Iran [ 222 ], and India [ 223 ].…”

“…It may be associated with tinnitus, but speech perception is typically good [ 11 ]. Interestingly, although Wolframin is equally expressed in the basal and apical turns of the cochlea, HL involves the low frequencies in DFNA6/14/38 and the high frequencies in Wolfram syndrome [ 191 ].…”