Recurrent de novo WFS1 pathogenic variants in Chinese sporadic patients with nonsyndromic sensorineural hearing loss

Abstract

Background Hereditary 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. Methods We 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. Results We 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. Conclusions We 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.

Cochlear Implantation Outcomes in Patients with Auditory Neuropathy Spectrum Disorder of Genetic and Non-Genetic Etiologies: A Multicenter Study

“…WFS1 is predominantly expressed in the spiral ganglion neuron [ 37 , 38 ], and impaired WFS1 function is related to the “postsynaptic” ANSD. Patients with WFS1 variants have been reported to have favorable outcomes after cochlear implantation [ 39 , 40 ]. Our patient with the WFS1 c.2051C>T (p.A684V) variant also exhibited good auditory and speech performances with CI.…”

WFS1 autosomal dominant variants linked with hearing loss: update on structural analysis and cochlear implant outcome

“…p.Ala684Val, a known mutational hotspot allele, often arose from de novo variants. The mode of inheritance of p.Ala684Val appears to be consistent among ethnic backgrounds, including Caucasian, Japanese, Chinese, and Taiwanese patients [ 19 , 47 , 57 , 58 ]. Putatively, fetuses with developmentally induced de novo variants may be at risk for more severe auditory phenotypes, necessitating CI at an early stage.…”

A Wolfram-like syndrome family: Case report

“…In this case, we found a heterozygous missense pathogenic variant c.2590G > A, (p. Glu864Lys) in the WFS1 gene, which has been described previously. [6][7][8] These studies described that patients carrying this pathogenic variant were manifested as deafness and diabetes mellitus, so some researchers named it autosomal dominant transmission of DM and HI. [6][7][8] Masafumi K et al identified three pathogenic variants (p. A684 V, p. K836N, and p. E864 K) known to cause Wolfram-like syndrome from 8 variants.…”