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.

Keywords: DFNA6/14/38; WFS1; autosomal dominant hearing loss; genotype; hereditary hearing loss; human genetics; likely pathogenic variant; low-frequency sensorineural hearing loss; phenotype.

Figure 1

Pedigree of family W21-1472 and co-segregation of the WFS1 variant with HL. The clinical status of the individuals is indicated by the filling of the symbols: black indicates that the subject has hearing loss, white indicates that the subject has no hearing loss and grey filling refers to an unknown status of hearing. The clinical status is based on audiograms in all participating subjects (with variant status V/+ or +/+) and in III:16 and V:01 (marked with an asterisk), who did not participate but provided an audiogram and who did participate but was not genetically tested, respectively. The clinical status of all other individuals is based on hetero-anamneses. Subject III:21 has a distinctive high frequency (hf) hearing loss phenotype. V, WFS1 variant (c.2512C>T p.(Pro838Ser)); +, wildtype; square, male; circle, female; slash through symbol, deceased; arrow, index case.

Figure 2

Audiologic features of DFNA6/14/38 subjects from family W21-1472. (A) The pure tone air conduction thresholds in dB HL of 0.25 to 8 kHz of all subjects identified with the WFS1 (c.2512C>T p.(Pro838Ser)) variant (III:02, III:04, III:11, III:13, III:25, III:27, IV:03, IV:07, IV:09, IV:13 and V:04) and subject V:01 who was not genetically tested. Black lines with circles represent the right ear, black lines with crosses represent the left ear, grey lines and dots represent the age- and gender-specific 95th percentile. (B) Mean audiogram with a 95% confidence interval. (C) Age-related typical audiograms (ARTA), derived from cross-sectional linear regression analysis of the most recent audiograms of DFNA6/14/38 subjects. Each line represents a ten-year age span. dB HL, decibel hearing level; f, female; kHz, kilo hertz; m, male; y, years.

Figure 3

Performance–age (a) and performance–impairment (b) plots. Cross-sectional analyses are shown in a performance–age plot of means (of both ears) of percentage correct phoneme recognition scores relative to age in years (a) and a performance–impairment plot of the same scores relative to pure tone averages (PTA) of 0.5 to 2 kHz (PTA_{0.5–2 kHz}) in dB HL (b). Panel (A) shows an onset age of deterioration of speech perception of 58 years. Panel (B) shows an onset level of deterioration of speech perception of 58 dB HL (PTA_{0.5–2 kHz}). Continuous lines are linear regression lines; dotted lines relate to 90% correct scores. dB HL, decibel hearing level; PTA, pure tone averages; y, years.