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
OBJECTIVE: The aim of this study was to elucidate the involvement of mutations in three relatively common deafness genes in Mexican individuals with non-syndromic hearing loss. METHODS: We sequenced GJB2 for mutations, screened for two deletions involving GJB6, del(GJB6-D13S1830) and del(GJB6-D13S1854), and for the m.1555A>G mutation in the MTRNR1 gene in 76 (71 simplex and 5 multiplex) unrelated Mexican probands with prelingual non-syndromic hearing loss. Samples were obtained from the Department of Genetics at Instituto Nacional de Rehabilitacion in Mexico City. RESULTS: Eight previously reported pathogenic variants and two polymorphic variants in GJB2 were identified. The two screened GJB6 deletions and the m.1555A>G mutation were not detected. Eight cases (10.6%) were found to have bi-allelic mutations in GJB2 and six (7.9%) were found to have a monoallelic GJB2 mutation. Of the six monoallelic mutations, one (p.R184Q) was a previously reported autosomal dominant variant. The most frequent pathological allele detected in this population was the c.35delG mutation in the GJB2 gene. The p.V27I polymorphic variant was also detected, with an allele frequency of 0.24. All eight probands with GJB2 mutations had symmetric profound deafness, whereas patients without GJB2 mutations had moderate, severe or profound hearing loss. CONCLUSIONS: This study shows that GJB2 mutations are an important cause of prelingual deafness in the Mexican population.
Assuntos
Conexinas/genética , Perda Auditiva/genética , Mutação , Conexina 26 , Conexina 30 , Surdez/genética , Deleção de Genes , Frequência do Gene , Heterozigoto , Humanos , México , Polimorfismo GenéticoRESUMO
Constitutional mutations in the RB1 gene predispose to retinoblastoma development. Hence genetic screening of retinoblastoma patients and relatives is important for genetic counseling purposes. In addition, RB1 gene mutation studies may help decipher the molecular mechanisms leading to tumors with different degrees of penetrance or expressivity. In the course of genetically screening of 107 hereditary and non-hereditary retinoblastoma patients (11 familiar bilateral, 4 familiar unilateral, 49 sporadic bilateral and 43 sporadic unilateral) and kindred from Spain, Colombia and Cuba, using direct PCR sequencing, we observed 45 distinct mutations and four RB1 deletions in 53 patients (9 familiar bilateral, 2 familiar unilateral, 31 sporadic bilateral and 11 sporadic unilateral). Most of these mutations (26/45, 57%) have not been reported before. In 32 patients, the predisposing mutations correspond to nonsense (mainly CpG transitions) and small insertions or deletions whose expected outcome is a truncated Rb protein that lacks the functional pockets and tail. Five single aminoacid replacements and seventeen mutations affecting splicing sites were also observed in retinoblastoma patients. Two of these sixteen mutations are of unclear pathogenic nature.
Assuntos
Mutação , Proteína do Retinoblastoma/genética , Retinoblastoma/genética , Colômbia , Cuba , Análise Mutacional de DNA , Éxons , Genes do Retinoblastoma , Genótipo , Humanos , Mutação de Sentido Incorreto , Fenótipo , Splicing de RNA/genética , EspanhaRESUMO
Para valorar la frecuencia de la sordera neurosensorial, bilateral, prelocutiva, severo-profunda, causada por mutaciones en el gen C´26 en el medio, se estudiaron a 35 pacientes procedentes de sorderas familiares y esporádicas. Se buscaron mutaciones en el gen de la conexina 26 (C´26) en un individuo afectado de cada familia y en todos los casos esporádicos o de causa no precesada (ENP). Se encontraron los 2 alelos mutados del gen en el 53,3 por ciento (8/15) de las familias autosómicas recesivas y en el 40 por ciento (6/15) de los pacientes ENP. El 65 por ciento del total de alelos mutados presentaron la mutación 35delG. No se hallaron mutaciones en los individuos procedentes de las familias autosómicas dominantes. En esta casuística las mutaciones en el gen de la C´26 fueron responsables del 40 por ciento (14/35) de los casos no relacionados con sordera neurosensorial no sindrómica severo-profunda.
Assuntos
Conexinas , Mutação , Perda Auditiva Neurossensorial/genéticaRESUMO
Las mutaciones del gen de la conexina 26 (locus DFNB1, en el brazo largo del cromosoma 13) dan cuenta de 60 porciento de las familias con sorderas neurosensoriales no sindrómicas autosómicas recesivas en poblaciones caucásicas. La prueba para la detección de la mutación 35delG, el análisis de heteroduplex y la secuenciación de la región codificante del gen de la conexina 26 en miembros de 15 familias cubanas con este tipo de sordera, arrojaron los resultados siguientes: en 10 de 15 familias (66,66 porciento) se observaron mutaciones en ambos alelos de la conexina 26, por lo que se clasificaron como sorderas tipo DFNB1. en estas familias DFNB1, 25/32 cromosomas analizados contenían la mutación 35deIG para una frecuencia de 0,781. Las mutaciones E47X y W77R se observaron en heterocigosis con la 35deIG. En 2 hipoacúsicos se detectaron también en heterocigosis las mutaciones puntuales M34T/R143W y V95M/R184P, respectivamente. Los hallazgos permitieron apreciar la alta frecuencia del tipo de sordera DFNB1 entre las sorderas no sindrómicas autosómicas recesivas que existían en la población cubana. El aspecto más destacable de la investigación es la similitud de sus resultados con los encontrados en poblaciones caucásicas relacionadas con el origen étnico de la población cubana. Este trabajo constituye la primera comunicación de estos estudios en el medio cubano
Assuntos
Humanos , Alelos , Cromossomos Humanos Par 13 , Cuba , Surdez , MutaçãoRESUMO
El cáncer de mama es la neoplasia más frecuente entre las mujeres. Una porción de aproximadamente el 10 por ciento de estos cánceres son causados por mutaciones germinales que pueden ser transmitidas de padres a hijos, son los llamados cánceres hereditarios. Las mutaciones germinales de al menos 2 genes supresores tumorales, los BRCA1 y BRCA2, cuentan aproximadamente el 85 por ciento de todos los cánceres hereditarios. En las familias con estas mutaciones es frecuente la aparición de cáncer de mama en miembros de generaciones sucesivas. Dada la importancia de identificar esas familias tanto para la práctica clínica con fines de lograr diagnósticos tempranos, como para la investigación de los genes implicados en el proceso tumoral, se creó con la colaboración del Servicio de Mastología del Instituto Nacional de Oncología y Radiobiología, un Registro de Cáncer de Mama Hereditario, del cual se muestran 3 familias que evidencian la transmisión del factor genético a través de varias generaciones.
Assuntos
Humanos , Feminino , Neoplasias da Mama , Linhagem , Sistema de RegistrosRESUMO
Se presenta una familia cubana con 5 miembros afectados por una hipoacusia bilateral, congénita, severa, mixta con componente neurosensorial predominante y sin alteraciones morfológicas de oído interno. El patrón de transmisión era compatible con la herencia recesiva ligada al cromosoma X. Los estudios moleculares detectaron una deleción en la región Xq21.1 que implica el gen POU3F4, responsable de la sordera de tipo DFN3. Se hacen comentarios sobre la evidente variabilidad clínica de las sorderas tipo DFN3