Genetic analysis of TMPRSS3 gene in the Korean population with autosomal recessive nonsyndromic hearing loss

The TMPRSS3 gene (DFNB8/10), which encodes a transmembrane serine protease, is a common hearing loss gene in several populations. Accurate functions of TMPRSS3 in the hearing pathway are still unknown, but TMPRSS3 has been reported to play a crucial role in inner ear development or maintenance. To date, 16 pathogenic mutations have been identified in many countries, but no mutational studies of the TMPRSS3 gene have been conducted in the Korean hearing loss population. In this study, we performed genetic analysis of TMPRSS3 in 40 unrelated Korean patients with autosomal recessive hearing loss to identify the aspect and frequency of TMPRSS3 gene mutations in the Korean population. A total of 22 variations were detected, including a novel variant (p.V291L) and a previously reported pathogenic mutation (p.A306T). The p.A306T mutation which has been detected in only compound heterozygous state in previous studies was identified in homozygous state for the first time in this study. Moreover, the clinical evaluation identified bilateral dilated vestibules in the patient with p.A306T mutation, and it suggested that p.A306T mutation of the TMPRSS3 gene might be associated with vestibular anomalies. In conclusion, this study investigated that only 2.5% of patients with autosomal recessive hearing loss were related to TMPRSS3 mutations suggesting low prevalence of TMPRSS3 gene in Korean hearing loss population. Also, it will provide the information of genotype–phenotype correlation to understand definite role of TMPRSS3 in the auditory system.     

Homozygosity mapping identifies a novel GIPC3 mutation causing congenital nonsyndromic hearing loss in a Saudi family

Hearing loss is one of the most common sensory disorders in humans and has a genetic cause in 50% of the cases. Our recent studies indicate that nonsyndromic hearing loss (NSHL) in the Saudi Arabian population is genetically heterogeneous and is not caused by mutations in GJB2 and GJB6, the most common genes for deafness in various populations worldwide. Identification of the causative gene/mutation in affected families is difficult due to extreme genetic heterogeneity and lack of phenotypic variability. We utilized an SNP array-based whole-genome homozygosity mapping approach in search of the causative gene, for the phenotype in a consanguineous Saudi family, with five affected individuals presenting severe to profound congenital NSHL. A single shared block of homozygosity was identified on chromosome 19p13.3 encompassing GIPC3, a recently identified hearing loss gene. Subsequently, a novel mutation c.122 C>A (p.T41K) in GIPC3 was found. This is the first report of GIPC3 mutation in a Saudi family. The presence of the GIPC3 mutations in only one of 100 Saudi families with congenital NSHL suggests that it appears to be a rare cause of familial or sporadic deafness in this population.     

Update of the spectrum of GJB2 gene mutations in Tunisian families with autosomal recessive nonsyndromic hearing loss

Hearing loss is the most frequent sensory disorder. It affects 3 in 1000 newborns. It is genetically heterogeneous with 60 causally-related genes identified to date. Mutations in GJB2 gene account for half of all cases of non-syndromic deafness. The aim of this study was to determine the relative frequency of GJB2 allele variants in Tunisia. In this study, we screened 138 patients with congenital hearing loss belonging to 131 families originating from different parts of Tunisia for mutations in GJB2 gene. GJB2 mutations were found in 39% of families (51/131). The most common mutation was c.35delG accounting for 35% of all cases (46/131). The second most frequent mutation was p.E47X present in 3.8% of families. Four identified mutations in our cohort have not been reported in Tunisia; p.V37I, c.235delC, p.G130A and the splice site mutation IVS1+1G>A (0.76%). These previously described mutations were detected only in families originating from Northern and not from other geographical regions in Tunisia. In conclusion we have confirmed the high frequency of c.35delG in Tunisia which represents 85.4% of all GJB2 mutant alleles. We have also extended the mutational spectrum of GJB2 gene in Tunisia and revealed a more pronounced allelic heterogeneity in the North compared to the rest of the country.     

Hereditary hearing loss: a 96 gene targeted sequencing protocol reveals novel alleles in a series of Italian and Qatari patients

Deafness is a really common disorder in humans. It can begin at any age with any degree of severity. Hereditary hearing loss is characterized by a vast genetic heterogeneity with more than 140 loci described in humans but only 65 genes so far identified. Families affected by hearing impairment would have real advantages from an early molecular diagnosis that is of primary relevance in genetic counseling. In this perspective, here we report a family-based approach employing Ion Torrent DNA sequencing technology to analyze coding and UTR regions of 96 genes related to hearing function and loss in a first series of 12 families coming from Italy and Qatar. Using this approach we were able to find the causative gene in 4 out of these 12 families (33%). In particular 5 novel alleles were identified in the following genes LOXHD1, TMPRSS3, TECTA and MYO15A already associated with hearing impairment. Our study confirms the usefulness of a targeted sequencing approach despite larger numbers are required for further validation and for defining a molecular epidemiology picture of hearing loss in these two countries.