Abstract
We performed targeted re-sequencing to identify the genetic etiology of early-onset postlingual deafness and encountered a frequent TMPRSS3 allele harboring two variants in a cis configuration. We aimed to evaluate the pathogenicity of the allele. Among 88 cochlear implantees with autosomal recessive non-syndromic hearing loss, subjects with GJB2 and SLC26A4 mutations were excluded. Thirty-one probands manifesting early-onset postlingual deafness were sorted. Through targeted re-sequencing, we detected two families with a TMPRSS3 mutant allele containing p.V116M and p.V291L in a cis configuration, p.[p.V116M; p.V291L]. A minor allele frequency was calculated and proteolytic activity was measured. A p.[p.V116M; p.V291L] allele demonstrated a significantly higher frequency compared to normal controls and merited attention due to its high frequency (4.84%, 3/62). The first family showed a novel deleterious splice site variant—c.783-1G>A—in a trans allele, while the other showed homozygosity. The progression to deafness was noted within the first decade, suggesting DFNB10. The proteolytic activity was significantly reduced, confirming the severe pathogenicity. This frequent mutant allele significantly contributes to early-onset postlingual deafness in Koreans. For clinical implication and proper auditory rehabilitation, it is important to pay attention to this allele with a severe pathogenic potential.
Highlights
Hearing loss is one of the most common diseases in newborns [1]
Among the 67 genes mapped for non-syndromic autosomal recessive hearing loss, TMPRSS3 (MIM# 601072, NM_024022) has been determined to be a causative gene for autosomal recessive (DFNB8/10) sensorineural hearing loss (SNHL) [3]
A combination of two “severe” TMPRSS3 mutations with null protease activity in a trans configuration leads to profound deafness with prelingual onset (DFNB10), while the severe mutation—in combination with milder TMPRSS3 mutations with a significant residual protease activity—leads to a milder phenotype with postlingual onset (DFNB8) [8]
Summary
Hearing loss is one of the most common diseases in newborns [1]. It is estimated that in all reported cases of genetic hearing loss, syndromic hearing loss accounts for approximately 30% and non-syndromic sensorineural hearing loss (SNHL) for about 70% [2]. Among the 67 genes mapped for non-syndromic autosomal recessive hearing loss, TMPRSS3 (MIM# 601072, NM_024022) has been determined to be a causative gene for autosomal recessive (DFNB8/10) SNHL [3]. TMPRSS3 includes 13 exons and is located on chromosome 21q22.3 [5] Mutations in this gene have been shown to be related to two discrete auditory phenotypes, depending on the protease activities of mutant proteins [6]. We previously showed that among those Koreans with sporadic or autosomal recessive severe SNHL with significant residual low-frequency hearing that went away mostly during early childhood and early adolescent years, 11.2% carried the variants of this gene, suggesting that DFNB8, rather than DFNB10, is a more important TMPRSS3-related phenotype in Koreans [8]
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