Residual Hearing in DFNB1 Deafness and Its Clinical Implication in a Korean Population

Abstract

IntroductionThe contribution of Gap junction beta-2 protein (GJB2) to the genetic load of deafness and its mutation spectra vary among different ethnic groups.ObjectiveIn this study, the mutation spectrum and audiologic features of patients with GJB2 mutations were evaluated with a specific focus on residual hearing.MethodsAn initial cohort of 588 subjects from 304 families with varying degrees of hearing loss were collected at the otolaryngology clinics of Seoul National University Hospital and Seoul National University Bundang Hospital from September 2010 through January 2014. GJB2 sequencing was carried out for 130 probands with sporadic or autosomal recessive non syndromic hearing loss. The audiograms were evaluated in the GJB2 mutants.ResultsOf the 130 subjects, 22 (16.9%) were found to carry at least one mutant allele of GJB2. The c.235delC mutation was shown to have the most common allele frequency (39.0%) among GJB2 mutations, followed by p.R143W (26.8%) and p.V37I (9.8%). Among those probands without the p.V37I allele in a trans configuration who showed some degree of residual hearing, the mean air conduction thresholds at 250 and 500 Hz were 57 dB HL and 77.8 dB HL, respectively. The c.235delC mutation showed a particularly wide spectrum of hearing loss, from mild to profound and significantly better hearing thresholds at 250 Hz and 2k Hz than in the non-p.V37I and non-235delC nonsyndromic hearing loss and deafness 1(DFNB1) subjects.ConclusionDespite its reputation as the cause of severe to profound deafness, c.235delC, the most frequent DFNB1 mutation in our cohort, caused a wide range of hearing loss with some residual hearing in low frequencies. This finding can be of paramount help for prediction of low frequency hearing thresholds in very young DFNB1 patients and highlights the importance of soft surgery for cochlear implantation in these patients.

High Rates of Three Common GJB2 Mutations c.516G>C, c.-23+1G>A, c.235delC in Deaf Patients from Southern Siberia Are Due to the Founder Effect

“…According to numerous studies, c.235delC mutation prevails in patients with hearing loss in Asian populations (China, Japan, Mongolia, Korea) [ 4 , 7 , 8 , 9 , 11 , 12 , 14 , 37 , 59 , 62 ]. The founder effect, implying the origin of c.235delC from a common ancestor, was suggested for the explanation of high prevalence of c.235delC in Asia.…”

“…Specific ethno-geographic prevalence patterns were found for many of them [ 3 , 4 , 5 ]. For instance, variant c.35delG (p.Gly12Valfs*2) is prevalent in deaf patients of Caucasian origin [ 3 , 6 ]; c.235delC (p.Leu79Cysfs*3) is common in some Asian populations [ 4 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]; c.167delT (p.Leu56Argfs*26) is frequent in Ashkenazi Jews [ 15 , 16 ]; c.427C>T (p.Arg143Trp) is specific for population of Ghana (West Africa) and Peru (South America) [ 17 , 18 ]; c.71G>A (p.Trp24*) is widely spread in Indians and European Gypsies [ 19 , 20 , 21 ]; c.109G>A (p.Val37Ile) prevails in populations of Southeast Asia [ 5 ]; the splice donor variant c.-23+1G>A was found in many populations worldwide but extremely high prevalence of c.-23+1G>A was detected among Yakuts (Eastern Siberia, Russia) [ 22 ]; c.131G>A (p.Trp44*) was found with high frequency among descendants of ancestral Mayan population in Guatemala [ 23 ].…”

Spectrum and Frequency of the GJB2 Gene Pathogenic Variants in a Large Cohort of Patients with Hearing Impairment Living in a Subarctic Region of Russia (the Sakha Republic)

“…These findings confirm our earlier reported data on the high prevalence of the c.-23+1G>A pathogenic variant among the Yakut population in Eastern Siberia [ 84 ]. Interestingly, in the Yakut patients, the second most common pathogenic variant was c.109G>A (p.Val37Ile), which was found with high frequency in Southeast Asia (Thailand, Indonesia, Malaysia) [ 41 , 47 , 48 ], East Asia (China, Korea, Japan) [ 33 , 35 – 38 , 40 , 42 , 44 , 46 ], and Australia [ 71 ], as well as among patients with HI of Asian origin in the US [ 87 ]. Pathogenic variants с.35delG (22.34%), c.-23+1G>A (5.31%), and c.313_326del14 (2.12%) were the most frequent in the group of Russian patients.…”

Large scale newborn deafness genetic screening of 142,417 neonates in Wuhan, China

“…It remains unanswered what is the most efficient and reliable means of identifying hearing loss related genetic variants in a public health effort. Next-generation sequencing (NGS) can be an effective tool for identifying known and novel variants related with hearing loss[ 32 ], but the cost and complexity of analysis may limit its applications to community level health care delivery, especially in developing regions. Chip based assays may be more cost effective, but it is difficult to add novel genetic loci related to hearing loss, the number of which are continually growing[ 30 , 32 ].…”

“…Next-generation sequencing (NGS) can be an effective tool for identifying known and novel variants related with hearing loss[ 32 ], but the cost and complexity of analysis may limit its applications to community level health care delivery, especially in developing regions. Chip based assays may be more cost effective, but it is difficult to add novel genetic loci related to hearing loss, the number of which are continually growing[ 30 , 32 ]. PCR is highly cost effective for a small number of variants and samples, readily adoptable in a variety of health care delivery sites, and assays specifically targeted towards variants associated with NSHL have been approved for use in clinical diagnoses[ 33 ].…”