Tímea Tóth

GJB2 Mutations and Degree of Hearing Loss: A Multicenter Study

Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mild-to-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (P<.0001). The HI of 48 different genotypes was less severe than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mild-to-moderate HI (median 25-40 dB). Two genotypes--35delG/R143W (median 105 dB) and 35delG/dela(GJB6-D13S1830) (median 108 dB)--had significantly more-severe HI than that of 35delG homozygotes.

Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations

Abstract. Hereditary hearing impairment is an extremely heterogeneous trait, with more than 70 identified loci. Only two of these loci are associated with an auditory phenotype that predominantly affects the low frequencies (DFNA1 and DFNA6/14). In this study, we have completed mutation screening of the WFS1 gene in eight autosomal dominant families and twelve sporadic cases in which affected persons have low-frequency sensorineural hearing impairment (LFSNHI). Mutations in this gene are known to be responsible for Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), which is an autosomal recessive trait. We have identified seven missense mutations and a single amino acid deletion affecting conserved amino acids in six families and one sporadic case, indicating that mutations in WFS1 are a major cause of inherited but not sporadic low-frequency hearing impairment. Among the ten WFS1 mutations reported in LFSNHI, none is expected to lead to premature protein truncation, and nine cluster in the C-terminal protein domain. In contrast, 64% of the Wolfram syndrome mutations are inactivating. Our results indicate that only non-inactivating mutations in WFS1 are responsible for non-syndromic low-frequency hearing impairment.

Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene

Hereditary hearing loss (HL) is a very heterogeneous trait, with 46 gene identifications for non-syndromic HL. Mutations in GJB2 cause up to half of all cases of severe-to-profound congenital autosomal recessive non-syndromic HL, with 35delG being the most frequent mutation in Caucasians. Although a genotype–phenotype correlation has been established for most GJB2 genotypes, the HL of 35delG homozygous patients is mild to profound. We hypothesise that this phenotypic variability is at least partly caused by the influence of modifier genes. By performing a whole-genome association (WGA) study on 35delG homozygotes, we sought to identify modifier genes. The association study was performed by comparing the genotypes of mild/moderate cases and profound cases. The first analysis included a pooling-based WGA study of a first set of 255 samples by using both the Illumina 550K and Affymetrix 500K chips. This analysis resulted in a ranking of all analysed single-nucleotide polymorphisms (SNPs) according to their P-values. The top 250 most significantly associated SNPs were genotyped individually in the same sample set. All 192 SNPs that still had significant P-values were genotyped in a second independent set of 297 samples for replication. The significant P-values were replicated in nine SNPs, with combined P-values between 3 × 10−3 and 1 × 10−4. This study suggests that the phenotypic variability in 35delG homozygous patients cannot be explained by the effect of one major modifier gene. Significantly associated SNPs may reflect a small modifying effect on the phenotype. Increasing the power of the study will be of greatest importance to confirm these results.

Phänotypische Charakterisierung schwerhöriger Patienten mit homozygoter 35delG-Mutation im Connexin-26-Gen

ZusammenfassungHintergrund. Hereditäre Schwerhörigkeit ist eine heterogene Erkrankung, die klinisch in syndromale und nichtsyndromale Hörstörungen unterteilt wird und phänotypisch von der geringgradigen bis an Taubheit grenzende Schwerhörigkeit variieren kann. Mutationen im GJB2-Gen, welches für ein Gap-Junction-Protein kodiert, sind für bis zu 50% der rezessiven hereditären Form der Schwerhörigkeit und für 10–35% aller sporadischen Fälle verantwortlich.Methoden. Wir haben 14 Familien und 69 sporadische Fälle aus der nordöstlichen Region Ungarns molekulargenetisch auf die sehr häufige 35delG-Mutation im GJB2-Gen untersucht. 65 für diese Mutation homozygote Patienten wurden in dieser Arbeit audiologisch charakterisiert.Ergebnisse. Ungefähr 70% aller untersuchten Personen zeigten eine prälinguale, sensorineurale, bilaterale, symmetrische Schwerhörigkeit ohne Progression. Die Audiogramme zeigten dabei entweder eine abfallende oder flache Konfiguration in nahezu gleichen Anteilen.Schlussfolgerung. Der Schweregrad der Erkrankung war in ca. 30% der Patienten unterschiedlich ausgeprägt, was die genetische Beratung Betroffener extrem erschwert.AbstractBackground. Hereditary hearing impairment constitutes a heterogeneous class of disorders showing different patterns of inheritance and involving multiple genes. Mutations in the GJB2 gene, especially the 35delG mutation, have been established as a major cause of inherited and sporadic nonsyndromic hearing impairment in different populations.Methods. We analyzed 14 northeast Hungarian families and 69 sporadic cases with nonsyndromic hearing impairment for the 35delG mutation. Sixty-five patients showing a homozygous 35delG mutation were examined regarding their audiologic phenotype.Results. In general, these patients (70%) showed a prelingual, sensorineural, bilateral, symmetric hearing impairment without progression. The audiograms demonstrated sloping as well as flat patterns.Conclusions. The severity of hearing impairment varied in 30% of all analyzed patients, making genetic counseling difficult.BACKGROUND Hereditary hearing impairment constitutes a heterogeneous class of disorders showing different patterns of inheritance and involving multiple genes. Mutations in the GJB2 gene, especially the 35delG mutation, have been established as a major cause of inherited and sporadic nonsyndromic hearing impairment in different populations. METHODS We analyzed 14 northeast Hungarian families and 69 sporadic cases with nonsyndromic hearing impairment for the 35delG mutation. Sixty-five patients showing a homozygous 35delG mutation were examined regarding their audiologic phenotype. RESULTS In general, these patients (70%) showed a prelingual, sensorineural, bilateral, symmetric hearing impairment without progression. The audiograms demonstrated sloping as well as flat patterns. CONCLUSIONS The severity of hearing impairment varied in 30% of all analyzed patients, making genetic counseling difficult.

Phenotype of patients showing hearing impairment based on the 35delG mutation in the connexin 26 gene

ZusammenfassungHintergrund. Hereditäre Schwerhörigkeit ist eine heterogene Erkrankung, die klinisch in syndromale und nichtsyndromale Hörstörungen unterteilt wird und phänotypisch von der geringgradigen bis an Taubheit grenzende Schwerhörigkeit variieren kann. Mutationen im GJB2-Gen, welches für ein Gap-Junction-Protein kodiert, sind für bis zu 50% der rezessiven hereditären Form der Schwerhörigkeit und für 10–35% aller sporadischen Fälle verantwortlich.Methoden. Wir haben 14 Familien und 69 sporadische Fälle aus der nordöstlichen Region Ungarns molekulargenetisch auf die sehr häufige 35delG-Mutation im GJB2-Gen untersucht. 65 für diese Mutation homozygote Patienten wurden in dieser Arbeit audiologisch charakterisiert.Ergebnisse. Ungefähr 70% aller untersuchten Personen zeigten eine prälinguale, sensorineurale, bilaterale, symmetrische Schwerhörigkeit ohne Progression. Die Audiogramme zeigten dabei entweder eine abfallende oder flache Konfiguration in nahezu gleichen Anteilen.Schlussfolgerung. Der Schweregrad der Erkrankung war in ca. 30% der Patienten unterschiedlich ausgeprägt, was die genetische Beratung Betroffener extrem erschwert.AbstractBackground. Hereditary hearing impairment constitutes a heterogeneous class of disorders showing different patterns of inheritance and involving multiple genes. Mutations in the GJB2 gene, especially the 35delG mutation, have been established as a major cause of inherited and sporadic nonsyndromic hearing impairment in different populations.Methods. We analyzed 14 northeast Hungarian families and 69 sporadic cases with nonsyndromic hearing impairment for the 35delG mutation. Sixty-five patients showing a homozygous 35delG mutation were examined regarding their audiologic phenotype.Results. In general, these patients (70%) showed a prelingual, sensorineural, bilateral, symmetric hearing impairment without progression. The audiograms demonstrated sloping as well as flat patterns.Conclusions. The severity of hearing impairment varied in 30% of all analyzed patients, making genetic counseling difficult.BACKGROUND Hereditary hearing impairment constitutes a heterogeneous class of disorders showing different patterns of inheritance and involving multiple genes. Mutations in the GJB2 gene, especially the 35delG mutation, have been established as a major cause of inherited and sporadic nonsyndromic hearing impairment in different populations. METHODS We analyzed 14 northeast Hungarian families and 69 sporadic cases with nonsyndromic hearing impairment for the 35delG mutation. Sixty-five patients showing a homozygous 35delG mutation were examined regarding their audiologic phenotype. RESULTS In general, these patients (70%) showed a prelingual, sensorineural, bilateral, symmetric hearing impairment without progression. The audiograms demonstrated sloping as well as flat patterns. CONCLUSIONS The severity of hearing impairment varied in 30% of all analyzed patients, making genetic counseling difficult.