RESUMO
OBJECTIVES: The genetics of sensorineural hearing loss is characterized by a high degree of heterogeneity. Despite this heterogeneity, DNA variants found within SLC26A4 have been reported to be the second most common contributor after those of GJB2 in many populations. METHODS: Whole exome sequencing and/or Sanger sequencing of SLC26A4 in 117 individuals with sensorineural hearing loss with or without inner ear anomalies but not with goiter from Turkey, Iran, and Mexico were performed. RESULTS: We identified 27 unique SLC26A4 variants in 31 probands. The variants c.1673A > G (p.N558S), c.1708-1G > A, c.1952C > T (p.P651L), and c.2090-1G > A have not been previously reported. The p.N558S variant was detected in two unrelated Mexican families. CONCLUSION: A range of SLC26A4 variants without a common recurrent mutation underlies SLC26A4-related hearing loss in Turkey, Iran, and Mexico.
Assuntos
Perda Auditiva Neurossensorial/genética , Proteínas de Membrana Transportadoras/genética , Orelha Interna/patologia , Feminino , Humanos , Irã (Geográfico) , Masculino , México , Mutação , Análise de Sequência de DNA , Transportadores de Sulfato , TurquiaRESUMO
INTRODUCTION: Branchio-oto-renal (BOR) syndrome is an autosomal dominant genetic disorder characterized by second branchial arch anomalies, hearing impairment, and renal malformations. Pathogenic mutations have been discovered in several genes such as EYA1, SIX5, and SIX1. However, nearly half of those affected reveal no pathogenic variant by traditional genetic testing. METHODS AND MATERIALS: Whole Exome sequencing and/or Sanger sequencing performed in 10 unrelated families from Turkey, Iran, Ecuador, and USA with BOR syndrome in this study. RESULTS: We identified causative DNA variants in six families including novel c.525delT, c.979T > C, and c.1768delG and a previously reported c.1779A > T variants in EYA1. Two large heterozygous deletions involving EYA1 were detected in additional two families. Whole exome sequencing did not reveal a causative variant in the remaining four families. CONCLUSIONS: A variety of DNA changes including large deletions underlie BOR syndrome in different populations, which can be detected with comprehensive genetic testing.
Assuntos
Síndrome Brânquio-Otorrenal/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Proteínas Tirosina Fosfatases/genética , Adulto , Pré-Escolar , Equador , Feminino , Humanos , Irã (Geográfico) , Masculino , Mutação , Linhagem , Análise de Sequência de DNA , Turquia , Estados UnidosRESUMO
Identifying the genetic etiology in a person with hearing loss (HL) is challenging due to the extreme genetic heterogeneity in HL and the population-specific variability. In this study, after excluding GJB2 variants, targeted resequencing of 180 deafness-related genes revealed the causative variants in 11 of 19 (58%) Brazilian probands with autosomal recessive HL. Identified pathogenic variants were in MYO15A (10 families) and CLDN14 (one family). Remarkably, the MYO15A p.(Val1400Met) variant was identified in eight families from the city of Monte Santo in the northeast region of Brazil. Haplotype analysis of this variant was consistent with a single founder. No other cases with this variant were detected among 105 simplex cases from other cities of northeastern Brazil, suggesting that this variant is confined to a geographical region. This study suggests that it is feasible to develop population-specific screening for deafness variants once causative variants are identified in different geographical groups.
Assuntos
Perda Auditiva/genética , Miosinas/genética , Brasil , Estudos de Casos e Controles , Claudinas/genética , Análise Mutacional de DNA , Efeito Fundador , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Mutação de Sentido IncorretoRESUMO
We report a child with hypoinsulinemic hypoglycemia and distinctive facies, with a diagnosis of the previously described MORFAN (Mental retardation, pre- and post-natal Overgrowth, Remarkable Face, and Acanthosis Nigricans) syndrome of unknown etiology. Whole-exome sequencing revealed a de novo AKT2 mutation. Although AKT2 has been implicated in four patients with hypoinsulinemic hypoglycemia, our report expands phenotypic spectrum to include MORFAN syndrome characteristics.