Cause Of Nonsyndromic Hearing Impairment Research Articles

Novel Pathogenic Variants in the Gene Encoding Stereocilin (STRC) Causing Non-Syndromic Moderate Hearing Loss in Spanish and Argentinean Subjects.

Non-syndromic hearing impairment (NSHI) is a very heterogeneous genetic condition, involving over 130 genes. Mutations in GJB2, encoding connexin-26, are a major cause of NSHI (the DFNB1 type), but few other genes have significant epidemiological contributions. Mutations in the STRC gene result in the DFNB16 type of autosomal recessive NSHI, a common cause of moderate hearing loss. STRC is located in a tandem duplicated region that includes the STRCP1 pseudogene, and so it is prone to rearrangements causing structural variations. Firstly, we screened a cohort of 122 Spanish familial cases of non-DFNB1 NSHI with at least two affected siblings and unaffected parents, and with different degrees of hearing loss (mild to profound). Secondly, we screened a cohort of 64 Spanish sporadic non-DFNB1 cases, and a cohort of 35 Argentinean non-DFNB1 cases, all of them with moderate hearing loss. Amplification of marker D15S784, massively parallel DNA sequencing, multiplex ligation-dependent probe amplification and long-range gene-specific PCR followed by Sanger sequencing were used to search and confirm single-nucleotide variants (SNVs) and deletions involving STRC. Causative variants were found in 13 Spanish familial cases (10.7%), 5 Spanish simplex cases (7.8%) and 2 Argentinean cases (5.7%). In all, 34 deleted alleles and 6 SNVs, 5 of which are novel. All affected subjects had moderate hearing impairment. Our results further support this strong genotype-phenotype correlation and highlight the significant contribution of STRC mutations to moderate NSHI in the Spanish population.

A novel autosomal dominant GREB1L variant associated with non-syndromic hearing impairment in Ghana

BackgroundChildhood hearing impairment (HI) is genetically heterogeneous with many implicated genes, however, only a few of these genes are reported in African populations.MethodsThis study used exome and Sanger sequencing to resolve the possible genetic cause of non-syndromic HI in a Ghanaian family.ResultsWe identified a novel variant c.3041G > A: p.(Gly1014Glu) in GREB1L (DFNA80) in the index case. The GREB1L: p.(Gly1014Glu) variant had a CADD score of 26.5 and was absent from human genomic databases such as TopMed and gnomAD. In silico homology protein modeling approaches displayed major structural differences between the wildtype and mutant proteins. Additionally, the variant was predicted to probably affect the secondary protein structure that may impact its function. Publicly available expression data shows a higher expression of Greb1L in the inner ear of mice during development and a reduced expression in adulthood, underscoring its importance in the development of the inner ear structures.ConclusionThis report on an African individual supports the association of GREB1L variant with non-syndromic HI and extended the evidence of the implication of GREB1L variants in HI in diverse populations.

Genetic mutations in patients with nonsyndromic hearing impairment of minority and Han Chinese ethnicities in Qinghai, China.

ObjectiveMutations in GJB2, SLC26A4, and mitochondrial (mt)DNA 12S rRNA genes are the main cause of nonsyndromic hearing impairment. The present study analyzed these mutations in ethnic minority and Han Chinese patients with nonsyndromic hearing impairment from Qinghai, China.MethodsThe SNPscan assay was used to analyze mutation spectra and frequencies in the two patient groups.ResultsGJB2 mutations were detected in 9.5% (20/210) of minority patients and 20.88% (48/230) of Han Chinese patients. The most common Han Chinese GJB2 variants were c.235delC and c.299_300delAT, whereas c.235delC and c.109G > A were the most prevalent in minority patients. SLC26A4 mutations were detected in 5.71% (12/210) of minority patients and 14.35% (33/230) of Han Chinese patients, and mtDNA 12S rRNA mutations were detected in 4.28% (9/210) of minority patients and 9.13% (21/230) of Han Chinese patients.ConclusionsThese data indicate that the mutation frequencies of three deafness-associated genes were significantly higher in Han Chinese patients than in minority patients. Moreover, the GJB2 mutation spectrum was shown to differ between these two patient groups.

Marital Structure, Genetic Fitness, and the GJB2 Gene Mutations among Deaf People in Yakutia (Eastern Siberia, Russia)

Autosomal recessive deafness type 1A (DFNB1A) caused by mutations in the GJB2 gene (Cx26) is the main cause of nonsyndromic hearing impairment in many populations worldwide. It is considered that widespread prevalence of DFNB1A can be due to the long tradition of intermarriages between deaf people (assortative marriages) combined with their increased social adaptation and genetic fitness after widespread introduction of sign language. For the first time, the data on mating structure and reproduction of deaf people living in Yakutia (Eastern Siberia, Russia) are presented in comparison with contribution of the GJB2 gene mutations to the etiology of hearing impairment. The relative fertility of deaf people compared to their hearing siblings is 0.78 (mean number of children 1.76 ± 0.10 and 2.24 ± 0.09 to deaf and their hearing siblings, respectively, p = 0.0018). The rate of assortative marriages among deaf people is 77.1% (81 of 105 marriages). Biallelic mutations in the GJB2 gene were found in 42.2% (43 of 102) of examined deaf people, which corresponded to diagnosis DFNB1A for these patients. A comparison of deaf marital partners by GJB2 status revealed a proportion of noncomplementary marriages (24%) in which hearing loss in both partners was caused by the presence of biallelic GJB2 gene mutations resulting in the birth of only deaf children in such couples. Thus, the set of obtained data including a relatively high genetic fitness (expressed as relative fertility) of deaf people in Yakutia in combination with a high rate of assortative marriages among them and high incidence of DFNB1A indicates a possible weakening of selection against such trait as “deafness” and a possible increase in the frequency of GJB2 mutant alleles in subsequent generations.

Evidence for Central Asian Origin of the p.Val27Ile Variant in the GJB2 Gene

The mutations in the GJB2 gene are the most common cause of nonsyndromic hearing impairment and they are associated with the population’s ethnic background. The p.Val27Ile is frequent in both Asia and America. In this retrospective study, we report the findings from the GJB2 screening and the audiological exams conducted on 125 Mexican mestizo patients with non-syndromic hearing impairment; they were treated at the Instituto Nacional de Rehabilitacion in Mexico City. The most frequent audiometric findings were bilateral, symmetrical, and profound hearing impairment. The allele frequencies in the GJB2 screening were p.Val27Ile 15%, other mutations 5%, and wild type 80%. We found no correlation between GJB2 genotype and auditory phenotype. The high allele frequency of p.Val27Ile was a very interesting finding. Our research suggests that p.Val27Ile arose in an ancient common ancestor who lived in Altai Republic and then the polymorphism was brought to America by its first inhabitants, the Amerindians. These results enhance our understanding of the peopling of the America, which remains unresolved.

The promoter mutation c.-259C>T (-3438C>T) is not a common cause of non-syndromic hearing impairment in Austria.

The objective of this study was to investigate the relevance of routine assessment of c.-259C>T in the Austrian newborn screening program. Homozygous and compound heterozygous mutations in the coding region of the human gene encoding gap junction protein GJB2 (Connexin 26) cause up to 50 % of neonatal autosomal recessive non-syndromic hearing impairment identified in Caucasian newborn screening programs. More recently, a null mutation in the GC box of the GJB2 basal promoter c.-259C>T has been described which causes hearing impairment by completely suppressing GJB2 promoter activity. We determined the occurrence of c.-259C>T in cases of non-syndromic hearing impairment lacking known pathogenic alterations in GJB2 (n = 43), a non-syndromic hearing impaired patient group (n = 15) bearing the heterozygous GJB2 mutations c.35delG, c.[79G>A];[341A>G] (p. [V27I];[E114G]), c.109G>A (p.V37I), c.154G>C (p.V52L), c.262G>T (p.A88S), c.269T>C (p.L90P) and c.551G>C (p.R184P) and in a normal hearing group lacking alterations in GJB2 (n = 50). In the analyzed groups, no occurrence of c.-259C>T was found. The c.-259C>T mutation, previously described as -3438C>T, is not a common cause of non-syndromic hearing impairment alone or together with heterozygous pathogenic GJB2 mutations that are statistically overrepresented in non-syndromic hearing impaired patient groups. Screening of newborns for c.-259C>T is therefore unlikely to be commonly found in Austrian NSHI patients but could make a significant contribution to non-syndromic hearing impairment in other populations.

The prevalence of the 235delC GJB2 mutation in a Chinese deaf population

PurposeMutations in the GJB2 gene are the most frequently found mutations in patients with nonsyndromic hearing impairment in populations studied to date. However, the prevalence of mutations varies among different ethnic groups. In most areas of China, genetic testing for nonsyndromic hearing impairment is currently not available because of the lack of information regarding the molecular cause of nonsyndromic hearing impairment. The purpose of this study is to determine the prevalence of a common GJB2 mutation, 235delC, in Chinese deaf children. MethodsWe collected DNA specimens from 3004 patients with nonsyndromic hearing impairment from 26 regions of China; 368 Han Chinese and 98 Uigur controls, and screened for the 235delC mutation. The coding exon of the GJB2 gene was polymerase chain reaction amplified, followed by restriction enzyme digestion with ApaI and analysis by agarose gel. ResultsOverall, 488 patients (16.3%) were determined to carry at least one 235delC mutant allele, with 233 (7.8%) homozygotes and 255 (8.5%) heterozygotes. Therefore, within the subpopulations examined, the frequency varies from 0% to 14.7% for 235delC homozygotes and from 1.7% to 16.1% for heterozygotes. On the basis of this survey of the patient cohort as stated, Chinese patients with nonsyndromic hearing impairment appear to have a relatively higher 235delC frequency than that of other Asian populations. ConclusionThese results demonstrate that an easy and fast genetic testing method for this well-known GJB2 gene mutation can be made available for at least 2 million Chinese patients and family members with nonsyndromic hearing impairment. By screening for the common GJB2 235delC mutation, the molecular cause in as high as 15% of patients with nonsyndromic hearing impairment in certain regions of China can be identified. In addition, patients who are negative for the 235delC mutation would be candidates for further mutational analysis of GJB2 or other deafness-related genes.

Involvement ofDFNB59 mutations in autosomal recessive nonsyndromic hearing impairment

In a consanguineous Turkish family, a locus for autosomal recessive nonsyndromic hearing impairment (ARNSHI) was mapped to chromosome 2q31.1-2q33.1. Microsatellite marker analysis in the complete family determined the critical linkage interval that overlapped with DFNB27, for which the causative gene has not yet been identified, and DFNB59, a recently described auditory neuropathy caused by missense mutations in the DFNB59 gene. The 352-amino acid (aa) DFNB59 gene product pejvakin is present in hair cells, supporting cells, spiral ganglion cells, and the first three relays of the afferent auditory pathway. A novel homozygous nonsense mutation (c.499C>T; p.R167X) was detected in the DFNB59 gene, segregating with the deafness in the family. The mRNA derived from the mutant allele was found not to be degraded in lymphocytes, indicating that a truncated pejvakin protein of 166 aa may be present in the affected individuals. Screening of 67 index patients from additional consanguineous Turkish families with autosomal recessive hearing impairment revealed a homozygous missense mutation (c.547C>T; p.R183W) that segregates with the hearing impairment in one family. Furthermore, in a panel of 83 Dutch patients, two additional novel mutations (c.509_512delCACT; p.S170CfsX35 and c.731T>G; p.L244R), which were not present in ethnically matched controls, were found heterozygously. Together, our data indicate that also nonsense mutations in DFNB59 cause nonsyndromic hearing loss, but that mutations in DFNB59 are not a major cause of nonsyndromic hearing impairment in the Turkish and Dutch population.

Prevalence of Cx26 (GJB2) Gene Mutations Causing Recessive Nonsyndromic Hearing Impairment in India

KEYWORDS NSHI; GJB2; W24X; mutation; India ABSTRACT Autosomal Recessive Nonsyndromic Hearing Impairment (ARNSHI) is caused by mutations in the gap junction gene GJB2 or Connexin26 gene (Cx26) in many of the world populations. In the present study screening of 200 probands with profound Nonsyndromic Hearing Impairment (NSHI) in comparison to 200 normal hearing controls from Andhra Pradesh, India revealed high prevalence of W24X mutation (6.5%) and low frequency of W77X (0.5%) and 235delC (0.5%) mutations. Incidence of 35delG and 167delT were not detected. High incidence of heterozygosity with R127H both in NSHI patients (28.0%) and in controls (36.5%) were observed indicating that the mutation could be a polymorphism and may not be the cause of NSHI. Two of the probands (1.0%) showed homozygosity for the mutation and causative nature of this mutation has to be evaluated. Cx26 mutations causing hearing impairment are found to be specific to certain populations exhibiting ethnic diversity.

Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns

Mutations in the GJB2 (connexin 26, Cx26) gene are the major cause of nonsyndromic hearing impairment in many populations. Genetic testing offers opportunities to determine the cause of deafness and predict the course of hearing, enabling the prognostication of language development. In the current study, we compared severity of hearing impairment in 60 patients associated with biallelic GJB2 mutations and assessed the correlation of genotypes and phenotypes. Within a spectrum of GJB2 mutations found in the Japanese population, the phenotype of the most prevalent mutation, 235delC, was found to show more severe hearing impairment than that of V37I, which is the second most frequent mutation. The results of the present study, taken together with phenotypes caused by other types of mutations, support the general rule that phenotypes caused by the truncating GJB2 mutations are more severe than those caused by missense mutations. The present in vitro study further confirmed that differences in phenotypes could be explained by the protein expression pattern.

GJB2 mutations in the Swiss hearing impaired.

Mutations in the GJB2 gene encoding connexin 26 (Cx26) protein are a major cause for nonsyndromic autosomal recessive and sporadic deafness. However, its contribution to hearing impairment in Switzerland remains undefined. To determine the frequency and type of GJB2 mutations in the Swiss hearing-impaired population diagnosed under the age of 2 yr and at 2 yr and older and to assess the effectiveness of denaturing high-performance liquid chromatography (DHPLC) in screening for mutation in GJB2. Thirty-four patients with hearing impairment underwent mutation screening of the single coding exon of GJB2 with DHPLC followed by bidirectional sequencing to identify sequence alterations. GJB2 mutations were more common in children diagnosed with hearing impairment under the age of 2 yr compared to the group 2 yr and older. In patients under age 2 yr, 9 of 20 (45%) harbored 13 GJB2 mutations including a common 313del14nt mutation; four of these patients were homozygous or compound heterozygous for GJB2 mutations. In contrast, 2 of 14 patients in the 2 yr and older group (14%) had a single mutation in GJB2. The 35delG mutation was exclusively found in 5 patients under the age of 2 yr. DHPLC for mutation screening was 100% sensitive and 83% specific for detecting sequence alterations in GJB2. In Switzerland, GJB2 mutations are a major cause of nonsyndromic hearing impairment in children under the age of 2. Similar to other populations, GJB2 mutations are uncommon in the affected Swiss patients identified after 2 yr. Although 35delG mutation is common in the hearing-impaired children under the age of 2, it was absent in patients diagnosed with hearing impairment after the age of 2. DHPLC is a highly sensitive tool for detection of GJB2 mutations.