RESUMO
INTRODUCTION: Mutations in GJB2 are the most common cause of non-syndromic autosomal recessive hearing impairment, ranging from mild to profound. Mutation analysis of this gene is widely available as a genetic diagnostic test. OBJECTIVE: To assess a possible genotype-phenotype correlation for GJB2. DESIGN: Retrospective analysis of audiometric data from people with hearing impairment, segregating two GJB2 mutations. SUBJECTS: Two hundred and seventy seven unrelated patients with hearing impairment who were seen at the ENT departments of local and university hospitals from Italy, Belgium, Spain, and the United States, and who harboured bi-allelic GJB2 mutations. RESULTS: We found that 35delG homozygotes have significantly more hearing impairment, compared with 35delG/non-35delG compound heterozygotes. People with two non-35delG mutations have even less hearing impairment. We observed a similar gradient of hearing impairment when we categorised mutations as inactivating (that is, stop mutations or frame shifts) or non-inactivating (that is, missense mutations). We demonstrated that certain mutation combinations (including the combination of 35delG with the missense mutations L90P, V37I, or the splice-site mutation IVS1+1G>A, and the V37I/V37I genotype) are associated with significantly less hearing impairment compared with 35delG homozygous genotypes. CONCLUSIONS: This study is the first large systematic analysis indicating that the GJB2 genotype has a major impact on the degree of hearing impairment, and identifying mild genotypes. Furthermore, this study shows that it will be possible to refine this correlation and extend it to additional genotypes. These data will be useful in evaluating habilitation options for people with GJB2 related deafness.
Assuntos
Conexinas/genética , Perda Auditiva/genética , Perda Auditiva/fisiopatologia , Mutação/genética , Adolescente , Adulto , Idade de Início , Idoso , Envelhecimento , Alelos , Audiometria , Bélgica , Criança , Pré-Escolar , Conexina 26 , Análise Mutacional de DNA , Progressão da Doença , Testes Genéticos , Genótipo , Perda Auditiva/classificação , Humanos , Lactente , Itália , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Espanha , Estados UnidosRESUMO
Genetic testing was completed on 1,294 persons with deafness referred to the Molecular Otolaryngology Research Laboratories to establish a diagnosis of DFNB1. Exon 2 of GJB2 was screened for coding sequence allele variants by denaturing high-performance liquid chromatography (DHPLC) complemented by bidirectional sequencing. If two deafness-causing mutations of GJB2 (encoding Connexin 26) were identified, further screening was not performed. If only a single deafness-causing mutation was identified, we screened for the g.1777179_2085947del (hereafter called del(GJB6-D13S1830); GenBank NT_024524.13) and mutations in the noncoding region of GJB2. Phenotype-genotype correlations were evaluated by categorizing mutations as either protein truncating or nontruncating. A total of 205 persons carried two GJB2 exon 2 mutations and were diagnosed as having DFNB1; 100 persons carried only a single deafness-causing allele variant of exon 2. A total of 37 of these persons were c.35delG carriers, and 51 carried other allele variants of GJB2. Persons diagnosed with DFNB1 segregating two truncating/nonsense mutations had a more severe phenotype than persons carrying two missense mutations, with mean hearing impairments being 88 and 37%, respectively (P < 0.05). The number of deaf c.35delG carriers was greater than expected when compared to the c.35delG carrier frequency in normal-hearing controls (P < 0.05), suggesting the existence of at least one other mutation outside the GJB2 coding region that does not complement GJB2 deafness-causing allele variants.
Assuntos
Conexinas/genética , Surdez/genética , Perda Auditiva Bilateral/genética , Mutação , Alelos , Audiometria de Tons Puros , Cromatografia Líquida de Alta Pressão , Conexina 26 , Conexinas/deficiência , Conexinas/fisiologia , Análise Mutacional de DNA/métodos , Surdez/classificação , Éxons/genética , Frequência do Gene , Genes Recessivos , Heterogeneidade Genética , Testes Genéticos , Genótipo , Perda Auditiva Bilateral/classificação , Humanos , Penetrância , Fenótipo , Polimorfismo Conformacional de Fita Simples , Sensibilidade e Especificidade , Análise de Sequência de DNA , Deleção de SequênciaRESUMO
BACKGROUND: This study reports the outcomes for patients with head and neck cancer who received reirradiation with palliative or curative intent. METHODS: A retrospective review of 41 patients treated with curative (n = 28) or palliative (n = 13) reirradiation was conducted. Survival was calculated from the start of the reirradiation. Radiation-related toxicities were classified according to Radiation Therapy Oncology Group criteria. Disease-related problems included adverse events during or after reirradiation that were not directly related to reirradiation. RESULTS: The observed 1-year survival for all patients was 39.0% (23.0% palliative, 46.3% curative). Median survival for all patients was 10.2 months. Seventy-five percent of curative and 53.8% of palliative patients had grade 3 or 4 radiation-related toxicities and/or major disease-related problems. CONCLUSION: A second course of radiotherapy in patients with head and neck cancer should be offered with a clear understanding that survival is poor and many of these patients will suffer severe radiation-related or disease-related insults to their quality of life during and after treatment.
Assuntos
Carcinoma/radioterapia , Neoplasias de Cabeça e Pescoço/radioterapia , Recidiva Local de Neoplasia/radioterapia , Idoso , Carcinoma/mortalidade , Carcinoma/patologia , Estudos de Coortes , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Cuidados Paliativos , Radioterapia/efeitos adversos , Retratamento/efeitos adversos , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Mutations in GJB2, the gene encoding connexin-26 at the DFNB1 locus on 13q12, are found in as many as 50% of subjects with autosomal recessive, nonsyndromic prelingual hearing impairment. However, genetic diagnosis is complicated by the fact that 10%-50% of affected subjects with GJB2 mutations carry only one mutant allele. Recently, a deletion truncating the GJB6 gene (encoding connexin-30), near GJB2 on 13q12, was shown to be the accompanying mutation in approximately 50% of these deaf GJB2 heterozygotes in a cohort of Spanish patients, thus becoming second only to 35delG at GJB2 as the most frequent mutation causing prelingual hearing impairment in Spain. Here, we present data from a multicenter study in nine countries that shows that the deletion is present in most of the screened populations, with higher frequencies in France, Spain, and Israel, where the percentages of unexplained GJB2 heterozygotes fell to 16.0%-20.9% after screening for the del(GJB6-D13S1830) mutation. Our results also suggest that additional mutations remain to be identified, either in DFNB1 or in other unlinked genes involved in epistatic interactions with GJB2. Analysis of haplotypes associated with the deletion revealed a founder effect in Ashkenazi Jews and also suggested a common founder for countries in Western Europe. These results have important implications for the diagnosis and counseling of families with DFNB1 deafness.