Genetic testing for hereditary hearing loss: Connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA)

Prasad, Sai; Cucci, Robert A.; Green, G.E.; Smith, Richard J.H.

doi:10.1002/1098-1004(200012)16:6<502::aid-humu7>3.0.co;2-4

Cited by 65 publications

(10 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Segregation of affected alleles within this family demonstrated that c.35delG is located on the second allele of this patient whereas mutation c.94C>A (R32C) occured in cis-location on the same chromosome. Mutation R32C was first described by Prasad and coworkers as disease related, recessive inherited DNA change (Prasad et al, 2000). Indeed, based on our results R32C more likely represents a polymorphism.…”

Section: Table1: Summary Of Gjb2 Sequence Variants Detected In Hungarsupporting

confidence: 69%

GJB2mutations in patients with non-syndromic hearing loss from Northeastern Hungary

Tóth¹,

Kupka²,

Haack³

et al. 2004

Hum. Mutat.

View full text Add to dashboard Cite

These authors contributed equally to this work. Communicated by Mark H. PaalmanMutations in the GJB2 gene encoding the gap-junction protein connexin 26 have been identified in many patients with childhood hearing impairment (HI). One single mutation, c.35delG, accounts for the majority of mutations in Caucasian patients with HI. In the present study we screened 500 healthy control individuals and a group of patients with HI from Northeastern Hungary for GJB2 mutations. The patients' group consisted of 102 familial from 28 families and 92 non-familial cases. The most common mutation in the Hungarian population is the c.35delG, followed by the c.71G>A (p.W24X) mutation. 34.3% of the patients in the familial group were homozygous, and 17.6% heterozygous for 35delG. In the non-familial group the respective values were 37% and 18% (allele frequency: 46.2%). In the general population an allele frequency of 2.4% was determined. Several patients were identified with additional, already described or new GJB2 mutations, mostly in heterozygous state. The mutation c.380G>A (p.R127H) was formerly found only in heterozygous state and its disease relation was controversial. We demonstrated the presence of this mutation in a family with three homozygous patients and 4 heterozygous unaffected family members, a clear indication of recessively inherited HI. Furthermore, we provided evidence for the pathogenic role of two new mutations, c.51C>A (p.S17Y) and c.177G>T (p.G59V), detected in the present study. In the latter case the pattern of inheritance might be dominant. Our results confirm the importance of GJB2 mutations in the Hungarian population displaying mutation frequencies that are comparable with those in the Mediterranean area.

show abstract

Section: Table1: Summary Of Gjb2 Sequence Variants Detected In Hungarsupporting

confidence: 69%

GJB2mutations in patients with non-syndromic hearing loss from Northeastern Hungary

Tóth¹,

Kupka²,

Haack³

et al. 2004

Hum. Mutat.

View full text Add to dashboard Cite

show abstract

“…However, the M34T allele was sometimes found as a compound heterozygote among individuals with hearing loss, 7,30,34,39,46,49 -52 and more rarely, in the homozygous form in individuals with hearing loss. 39,51,53 No changes have been reported in the other allele among the M34T carriers in the control groups. Thus, the evidence appears to support the hypothesis that M34T is a recessive allele, although the lack of compound heterozygotes in the control groups may be due to their smaller sample sizes.…”

Section: M34t Allele and Hearing Lossmentioning

confidence: 79%

GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: A HuGE review

Kenneson

Braun

Boyle

2002

Genetics in Medicine

352

323

View full text Add to dashboard Cite

Despite the enormous heterogeneity of genetic hearing loss, variants in one locus, Gap Junction Beta 2 or GJB2 (connexin 26), account for up to 50% of cases of nonsyndromic sensorineural hearing loss in some populations. This article reviews genetic epidemiology studies of the alleles of GJB2, prevalence rates, genotype-phenotype relations, contribution to the incidence of hearing loss, and other issues related to the clinical validity of genetic testing for GJB2. This review focuses primarily on three alleles: 167⌬T, 35⌬G, and 235⌬C. These alleles are recessive for nonsyndromic prelingual sensorineural hearing loss, and the evidence suggests complete penetrance but variable expressivity. GENEThe Gap Junction Beta 2 or GJB2 gene (GenBank M86849, OMIM: *121011) resides at the chromosomal location 13q11 and encodes for the protein connexin 26, a beta class gap junction protein expressed in the cochlea and in the epidermis. 3 Connexin 26 hexamers form channels between cells that, when open, allow cell-to-cell diffusion of small molecules. This function is necessary for recycling potassium in the cochlea that plays a critical role in sensorineural hearing function. 4 The GJB2 gene is small, with the entire coding region of 680 base pairs falling within exon 2. GENE VARIANTSAided by the relatively small size of the GJB2 gene, the flourish of activity on the genetics of hearing loss has resulted in rapid identification of GJB2 variants. Missense, nonsense, frameshift, insertion, and deletion variants have all been reported. To identify published genetic epidemiology studies related to GJB2, we searched the MEDLINE database using the keywords GJB2, connexin 26, and hearing loss to identify relevant studies. References in related studies were also reviewed.A list of GJB2 variants is presented in Table 1. Some variants are benign polymorphisms, with a high prevalence rate in various populations. For example, the V27I, E114G, and I203T variants were found on 54%, 55%, and 94% of Japanese chromosomes, respectively. 5,6 The 167⌬T, 35⌬G (also known as 30⌬G), 235⌬C, and R143W alleles are the most common hearing loss-associated GJB2 alleles in the Ashkenazi Jewish, Caucasian, Japanese, and Ghanian populations, respectively. The best-characterized population is Caucasian of northern European descent. Table 2 presents the heterozygote carrier frequencies of the first three alleles either in the general population (hearing status unknown) or in control groups (without hearing loss). Ascertainment details were generally lacking and are listed in Table 2 as described in the publication. Likewise, descriptive information, including sex and age, were generally not provided. Despite these limitations, the studies consistently reported a prevalence of the 35⌬G allele in the range of 1% to 3%. In fact, one population-based study, which genotyped 560 randomly selected neonatal bloodspots in the Midwestern United States, detected a 35⌬G heterozygosity rate of 2.5% in this predominantly Caucasian population. 7 In addition to Caucasians, ...

show abstract

“…Nevertheless, this amino acid residue appears to be important for normal function, as two other pathogenic mutations (R32C and R32H) responsible for hearing loss have been identified recently. 35,46 In fact, of all the amino acids in the TM1 domain, R32 is one of the most highly conserved (shares identity in all four human Cx26, Cx30, Cx31, Cx32; mice Cx30; and chicken Cx31) that has been implicated in hearing loss. These facts support the presumed pathogenicity of R32L.…”

Section: Cx26 Mutations In Childhood Deafnessmentioning

confidence: 99%

“…27,44,46,47 The supporting evidence for these mutations is limited: R127H was detected in an affected brother-sister pair, whereas F83L, G160S, and I203T occur at highly conserved residues. Therefore, it is not unreasonable to raise the question of whether these are pathogenic mutations.…”

Section: Cx26 Mutations In Childhood Deafnessmentioning

confidence: 99%

Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing

Lindeman

Lip

et al. 2002

Genetics in Medicine

View full text Add to dashboard Cite

Purpose: Hearing loss is a common congenital disorder that is frequently associated with mutations in the GJB2 gene encoding the connexin 26 protein (Cx26). We sought to evaluate the effectiveness of direct DNA sequencing for detection of Cx26 mutations as a clinical diagnostic test. Methods: We designed a clinical assay using a three-step polymerase chain reaction (PCR)-based DNA sequencing strategy to detect all possible mutations in the open reading frame and flanking sequences of Cx26. The results of the first 324 cases of childhood deafness referred for diagnostic testing were analyzed. Results: A total of 127 of the 324 (39.2%) cases had at least one mutant Cx26 allele (36.1% of sporadic cases, 70% of familial cases). Of these 127 case, 57 (44.8%) were homozygotes or compound heterozygotes. Thirty-four different mutations were identified, including 10 novel mutations, 6 of which (T8M, K15T, R32L, M93I, N206S, and 511-512insAACG) may be pathogenic. We also provide new evidence on the pathogenicity or nonpathogenicity of 12 previously reported mutations, and clarify the confusing nomenclature of the 313-326del14 mutation. Key Words: connexin 26 (GJB2), Cx26 mutation, congenital hearing loss, deafness, molecular diagnosticsHearing loss is a common congenital disorder, affecting 0.1% to 0.2% of all newborns. Of these cases,~60% are inherited and~80% of inherited deafness falls under the category of autosomal recessive, nonsyndromic hearing loss. 1-3 Within this category,~50% of severe to profound cases are classified as DFNB1 in the ethnic populations tested 4,5 and are caused by mutations in the GJB2 gene, 6 -9 which encodes the protein connexin 26 (Cx26), a member of the connexin family of proteins. These proteins are major constituents of intercellular gap junctions, and Cx26 is believed to play a crucial role in regulating potassium ion flux during auditory transduction in the inner ear. 10 -12 In addition, a few autosomal dominant deafnesscausing mutations in Cx26 have also been described, classified clinically as DFNA3. 5 Moreover, mutations in Cx26 (and in other connexins) have been associated with syndromic deafness, including Vohwinkel syndrome, palmoplantar keratoderma, and erythrokeratodermas. [13][14][15][16][17] Several studies have demonstrated a wide spectrum of Cx26 mutations associated with hearing loss in patients with a broad range of deafness. Although the most common mutation is 35delG, the prevalences and carrier frequencies of the different mutations vary among peoples of different ethnicities. 18 -32 Over 70 pathogenic recessive or dominant mutations, and close to 20 allelic variants with undetermined pathogenicity or polymorphisms, have been reported. [33][34][35] However, no clear genotype-phenotype correlations have been established. 36 -41 We report here the results of a sequence-based mutation analysis of the connexin 26 (GJB2) gene in blood samples from 324 children (and appropriate family members) sent for clinical molecular diagnostic testing for familial or sporadic deafn...

show abstract

Genetic testing for hereditary hearing loss: Connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA)

Cited by 65 publications

References 26 publications

GJB2mutations in patients with non-syndromic hearing loss from Northeastern Hungary

GJB2mutations in patients with non-syndromic hearing loss from Northeastern Hungary

GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: A HuGE review

Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing

Contact Info

Product

Resources

About