RESUMO

Sotos syndrome is characterized by overgrowth starting before birth through childhood with intellectual disability and craniofacial anomalies. The majority of patients are large for gestational age with developmental delay or intellectual disability. The majority of cases are caused by pathogenic variants in NSD1. The most consistent physical features in this disorder are facial dysmorphisms including prominent forehead, downslanted palpebral fissures, prognathism with a pointed chin, and a long and narrow face. We present a follow-up to a cohort of 11 individuals found to harbor heterozygous, pathogenic, or likely pathogenic variants in NSD1. We analyzed the facial dysmorphisms and the condition using retrospective over 20 years. Among these patients, followed in our medical genetics outpatient clinic for variable periods of time, all had a phenotype compatible with the characteristic Sotos syndrome facial features, which evolved with time and became superimposed with natural aging modifications. We present here a long-term follow-up of facial features of Brazilian patients with molecularly confirmed Sotos syndrome. In this largest Brazilian cohort of molecularly confirmed patients with Sotos syndrome to date, we provide a careful description of the facial phenotype, which becomes less pronounced with aging and possibly more difficult to recognize in adults. These results may have broad clinical implications for diagnosis and add to the global clinical delineation of this condition.

Assuntos

Anormalidades Craniofaciais/genética , Predisposição Genética para Doença , Histona-Lisina N-Metiltransferase/genética , Síndrome de Sotos/genética , Adolescente , Brasil/epidemiologia , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/fisiopatologia , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Face/diagnóstico por imagem , Face/fisiopatologia , Feminino , Seguimentos , Transtornos do Crescimento/complicações , Transtornos do Crescimento/genética , Transtornos do Crescimento/fisiopatologia , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Fenótipo , Síndrome de Sotos/diagnóstico por imagem , Síndrome de Sotos/fisiopatologia

RESUMO

Colorectal cancer is a leading cause of cancer that may metastasize. KRAS gene sequence of exon 2 should be examined for identification of patients that can be treated with anti-EGFR. The aim of the present study was to evaluate the efficacy of high-resolution melting (HRM) to detect KRAS mutations in colorectal cancer (CRC) tumors. The exon 2 of KRAS was amplified from 47 adenocarcinoma CRC tissues. The tumors were subjected to high-resolution melt using quantitative PCR to identify wild-type and mutant subgroups. The results were compared to the mutations detected by next-generation sequences (NGS). The study included 47 patients, with a mean age of 62 years, of whom 24 patients were male. Most of the patients had stage II or stage III tumors. The mean melting temperatures for the wild-type and mutated group at exon 2 were 78.13˚C and 77.87˚C, respectively (P<0.001, 95% CI = 0.11-0.4). The sensitivity and specificity of high-resolution melting were 83.3 and 96.6%, respectively, with a high concordance between the NGS and HRM methods for detecting KRAS mutation in exon 2 (ĸ = 0.816; P=0.625). Thus, HRM could be used as an alternative method for detecting KRAS mutations in colorectal cancer tissue.

RESUMO

Resumen Fundamento: la hiperplasia suprarrenal congénita constituye la causa más frecuente de ambigüedad sexual en la infancia y aproximadamente el 95 % de los casos son producto de mutaciones que ocurren en el gen que codifica la enzima 21α-hidroxilasa. El diagnóstico molecular constituye un elemento a considerar para el manejo y asesoramiento genético a pacientes y familiares en riesgo. Objetivo: identificar la mutación I172N, determinar su frecuencia en la población estudiada y su posible relación con los fenotipos clínicos encontrados. Métodos: se realizó un estudio descriptivo, de corte transversal, durante el período 2014-2016 a pacientes cubanos con diagnóstico de hiperplasia suprarrenal congénita por insuficiencia de 21-OH atendidos en el Instituto de Endocrinología de La Habana. El universo de estudio quedó constituido por 32 pacientes. Los resultados se presentaron en tablas o gráficos según fue más factible mostrar la información. Resultados: la mutación I172N fue identificada en individuos de ambos sexos y se estableció su relación con las formas clásicas de la enfermedad. En la población estudiada, se ubicó dentro de las tres mutaciones más frecuentes de las pesquisadas hasta el momento en el Centro Nacional de Genética Médica de la Habana a pacientes con hiperplasia suprarrenal congénita por insuficiencia de 21 OH. Conclusiones: el método estandarizado demostró ser reproducible y confiable para el diagnóstico molecular de los individuos con hiperplasia suprarrenal congénita por insuficiencia de 21-OH. La mutación I172N se ubica dentro de las tres más frecuentes en la población cubana estudiada y se relaciona con las formas clásicas de la enfermedad.

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ABSTRACT Background: congenital adrenal hyperplasia is the most frequent cause of sexual ambiguity in childhood. Molecular diagnosis is an element to be considered for the management and genetic counseling of patients and relatives at risk. Objective: to identify the I172N mutation, to determine its frequency in the studied population and its possible relationship with the clinical phenotypes found. Methods: a descriptive, cross-sectional study was conducted during the 2014-2016 period for Cuban patients diagnosed with congenital adrenal hyperplasia due to 21-OH insufficiency treated at the Institute of Endocrinology of Havana. The universe consisted of 32 patients. The variables analyzed were: age, social sex, age at diagnosis, clinical form of hyperplasia, diagnosis by screening program, family history, consanguinity, nonspecific neonatal death, genital crisis of the newborn, previous molecular diagnosis, mutations studied previously, mutation I172N gene CYP21A. The results were presented in tables or graphs as it was more feasible to show the information. Results: the I172N mutation was identified in individuals of both sexes and its relation with the classic forms of the disease was established. In the studied population the three most frequent mutations of the researched ones, so far in the National Center of Medical Genetics of Havana to patients with congenital adrenal hyperplasia due to 21 OH insufficiency. Conclusions: the standardized method proved to be reproducible and reliable for the molecular diagnosis of individuals with congenital adrenal hyperplasia due to 21-OH insufficiency. The I172N mutation is among the three most frequent in the studied Cuban population and is related to the classic forms of the disease.

RESUMO

INTRODUCTION: The risk of developing breast and ovarian cancer is higher in families that carry mutations in BRCA1 or BRCA2 genes, and timely mutation detection is critical. OBJECTIVE: To identify the presence of mutations in the Colombian population and evaluate two testing strategies. METHODS: From a total universe of 853 individual blood samples referred for BRCA1 and BRCA2 typing, 256 cases were analyzed by complete direct sequencing of both genes in Myriad Genetics, and the remaining 597 cases were studied by partial sequencing based on founder mutations in a PCR test designed by ourselves ("Profile Colombia"). RESULTS: We found 107 patients carrying deleterious mutations in this group of patients, 69 (64.5%) located in BRCA1, and 38 (35.5%) in BRCA2. Overall, we detected 39 previously unreported mutations in Colombia (22 in BRCA1 and 17 in BRCA2) and only 4 out of the 6 previously reported founder mutations. Sixty four out of 597 patients (10.7%) studied by "Profile Colombia" showed mutations in BRCA1 or BRCA2, and 41/256 patients (16%) showed mutations by complete BRCA1-BRCA2 sequencing. CONCLUSIONS: The spectrum of 44 different mutations in Colombia as detected in our study is broader than the one previously reported for this country. "Profile Colombia" is a useful screening test to establish both founder and new mutations (detection rate of 10.7%) in cases with family history of breast cancer. Complete sequencing shows a detection rate of 16.0%, and should complement the study of the genetic basis of this disease.

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INTRODUCCIÓN: El riesgo de desarrollar cáncer de mama y cáncer de ovario puede transmitirse en familias que porten mutaciones en los genes BRCA1 o BRCA2. La detección de estas mutaciones permite tomar decisiones oportunas en el ámbito de la medicina preventiva. OBJETIVO: Estudiar el espectro de mutaciones en la población colombiana y evaluar dos estrategias de detección. METODOS: Se incluyeron en total 853 pacientes con diagnóstico de cáncer de mama y con solicitud de análisis de los genes BRCA1 y BRCA2. Un total de 256 pruebas se analizaron mediante secuencia directa completa de estos genes en Myriad Genetics, y las restantes 597 se estudiaron mediante secuencia parcial basada en mutaciones fundadoras a través de la prueba "Perfil Colombia", implementada por nosotros. RESULTADOS: Se detectaron 107 pacientes portadores de mutaciones en pacientes colombianos, 69 de las cuales estaban localizadas en BRCA1 y 38 en BRCA2. De estas 39 mutaciones son nuevas (22 en BRCA1 y 17 en BRCA2) y solo se hallaron 4 de las 6 mutaciones reportadas previamente como fundadoras en Colombia. En 64/597 pacientes analizados mediante el "Perfil Colombia" se detectaron mutaciones en BRCA1 o BRCA2, así como en 41/256 pacientes que solicitaron la secuenciación completa de los genes BRCA1 y BRCA2. CONCLUSIONES: El espectro de mutaciones fundadoras en Colombia es más amplio que el reportado anteriormente para este país. El "Perfil Colombia" es una prueba que revela a la vez mutaciones fundadoras y mutaciones nuevas, con una tasa de detección del 10.7%. La secuenciación completa presenta una tasa de detección del 16.0% y puede complementar el diagnóstico de la base genética de esta enfermedad.

Assuntos

Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Colômbia , Feminino , Humanos , Programas de Rastreamento/métodos , Mutação , Análise de Sequência de DNA

RESUMO

Abstract Introduction: The risk of developing breast and ovarian cancer is higher in families that carry mutations in BRCA1 or BRCA2 genes, and timely mutation detection is critical. Objective: To identify the presence of mutations in the Colombian population and evaluate two testing strategies. Methods: From a total universe of 853 individual blood samples referred for BRCA1 and BRCA2 typing, 256 cases were analyzed by complete direct sequencing of both genes in Myriad Genetics, and the remaining 597 cases were studied by partial sequencing based on founder mutations in a PCR test designed by ourselves ("Profile Colombia"). Results: We found 107 patients carrying deleterious mutations in this group of patients, 69 (64.5%) located in BRCA1, and 38 (35.5%) in BRCA2. Overall, we detected 39 previously unreported mutations in Colombia (22 in BRCA1 and 17 in BRCA2) and only 4 out of the 6 previously reported founder mutations. Sixty four out of 597 patients (10.7%) studied by "Profile Colombia" showed mutations in BRCA1 or BRCA2, and 41/256 patients (16%) showed mutations by complete BRCA1-BRCA2 sequencing. Conclusions: The spectrum of 44 different mutations in Colombia as detected in our study is broader than the one previously reported for this country. "Profile Colombia" is a useful screening test to establish both founder and new mutations (detection rate of 10.7%) in cases with family history of breast cancer. Complete sequencing shows a detection rate of 16.0%, and should complement the study of the genetic basis of this disease.

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Resumen Introducción: El riesgo de desarrollar cáncer de mama y cáncer de ovario puede transmitirse en familias que porten mutaciones en los genes BRCA1 o BRCA2. La detección de estas mutaciones permite tomar decisiones oportunas en el ámbito de la medicina preventiva. Objetivo: Estudiar el espectro de mutaciones en la población colombiana y evaluar dos estrategias de detección. Metodos: Se incluyeron en total 853 pacientes con diagnóstico de cáncer de mama y con solicitud de análisis de los genes BRCA1 y BRCA2. Un total de 256 pruebas se analizaron mediante secuencia directa completa de estos genes en Myriad Genetics, y las restantes 597 se estudiaron mediante secuencia parcial basada en mutaciones fundadoras a través de la prueba "Perfil Colombia", implementada por nosotros. Resultados: Se detectaron 107 pacientes portadores de mutaciones en pacientes colombianos, 69 de las cuales estaban localizadas en BRCA1 y 38 en BRCA2. De estas 39 mutaciones son nuevas (22 en BRCA1 y 17 en BRCA2) y solo se hallaron 4 de las 6 mutaciones reportadas previamente como fundadoras en Colombia. En 64/597 pacientes analizados mediante el "Perfil Colombia" se detectaron mutaciones en BRCA1 o BRCA2, así como en 41/256 pacientes que solicitaron la secuenciación completa de los genes BRCA1 y BRCA2. Conclusiones: El espectro de mutaciones fundadoras en Colombia es más amplio que el reportado anteriormente para este país. El "Perfil Colombia" es una prueba que revela a la vez mutaciones fundadoras y mutaciones nuevas, con una tasa de detección del 10.7%. La secuenciación completa presenta una tasa de detección del 16.0% y puede complementar el diagnóstico de la base genética de esta enfermedad.

Assuntos

Feminino , Humanos , Neoplasias da Mama/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Programas de Rastreamento/métodos , Análise de Sequência de DNA , Colômbia , Mutação

RESUMO

IMPORTANCE: The importance of the study was to describe the clinical characteristics and mutational analysis of Mexican patients with aniridia. BACKGROUND: Aniridia is a panocular hereditary eye disease caused by mutations in the PAX6 transcription factor. Mutation detection rate is highly variable ranging from 30% to 90% in different populations. Very few studies have been published about the PAX6 mutational analysis in aniridia patients from Mexico. In order to establish a more representative PAX6 mutational frequency in the country, a cohort of 22 Mexican unrelated aniridia probands were analysed in this study. DESIGN: Case series. PARTICIPANTS: A total of 22 Mexican probands with bilateral isolated aniridia and their available relatives were included. METHODS: Sanger sequencing was used for the mutational analysis of all coding exons and flanking intronic regions of PAX6. MAIN OUTCOME MEASURES: Clinical characteristics and results of PAX6 mutational analysis in probands with aniridia and available family members. RESULTS: Molecular analysis of PAX6 in 22 index cases with aniridia allowed the identification of a total of 16 different mutations. Seven of these pathogenic variants are novel, including c.183C>G, p.(Y61*); c.718delC, p.(R240Efs*3); c.1149_1152delTCAG, p.(P385Wfs*139); c.257_266delAAATAGCCCA, p.(K86Sfs*35); c.836_843dupGCAACACA p.(P282Afs*86); c.1032+2_1032+3insT; and c.141+2T>A. Inter and intrafamilial phenotypic heterogeneity was found. CONCLUSIONS AND RELEVANCE: The mutational diagnostic rate in this series was 77%, which is comparable with reports from other populations. Importantly, no founder mutations were identified in this case series. Our results add 7 novel PAX6 pathogenic variants to the aniridia-related mutational spectrum and reveal considerable PAX6 allelic heterogeneity in this population.

Assuntos

Aniridia/genética , DNA/genética , Mutação , Fator de Transcrição PAX6/genética , Adolescente , Adulto , Alelos , Aniridia/epidemiologia , Aniridia/metabolismo , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Heterogeneidade Genética , Humanos , Incidência , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Fator de Transcrição PAX6/metabolismo , Fenótipo , Adulto Jovem

RESUMO

Neurofibromatosis type 1 (NF1), is a haploinsufficient and multisystemic disease, caused by inherited or sporadic mutations in the NF1 gene. Its incidence is one in 2,500 to 3,000 individuals, it has an autosomal dominant pattern of inheritance, high clinical variability, complete penetrance and age-dependent complications. Neurofibromin is the product of the NF1 gene and is believed to act as a tumor suppressor since the loss of its function has been associated with benign and malignant tumors in neural crest-derived tissues. Only two correlations between clinical phenotype and mutant alleles in the NF1 gene have been observed. The established criteria for disease diagnosis are very efficient in adults and children older than 3 years of age, but not for children under this age. Mutational analysis is therefore recommended to confirm the disease in young children with a negative family history. A pathogenic mutation in the NF1 should be added to the list of diagnostic criteria. Mutational analysis is also recommended for differential diagnosis and for prenatal or pre-implantation genetic diagnosis, taking into consideration the family history and the type of method to be applied. Molecular studies of this disease using different complimentary molecular techniques and bioinformatics tools have characterized NF1 gene mutations at both the DNA and mRNA levels, increasing the mutational spectrum. Consequently, about 1,289 defects have been reported to date, mainly nonsense/missense mutations, deletions and splice site defects.

Assuntos

Humanos , Análise Mutacional de DNA , Genes da Neurofibromatose 1 , Mutação/genética , Neurofibromatose 1/diagnóstico , Neurofibromina 1/genética , Alelos , Diagnóstico Diferencial , Diagnóstico Precoce , Neurofibromatose 1/genética , Penetrância , Fenótipo

RESUMO

Mucolipidosis III (ML III) gamma is a very rare autosomal-recessive disorder characterized by the abnormal trafficking and subcellular localization of lysosomal enzymes due to mutations in the GNPTG gene. The present study consists of a report of a Brazilian compound heterozygote patient with ML III gamma resulting from one mutant paternal allele and one allele that had most likely undergone a de novo or maternal germline mutation. This is the first report of a de novo mutation in ML III gamma. This finding has significant implications for genetic counseling.

RESUMO

We report the case of a 28-year-old woman with Kindler syndrome, a rare form of epidermolysis bullosa. Clinically, since childhood, she had widespread pigmentary changes in her skin as well as photosensitivity and fragility of the skin and mucous membranes. The mucosal involvement led to an erosive stomatitis as well as esophageal, anal and vaginal stenoses, requiring surgical intervention. The diagnosis of Kindler syndrome was confirmed by DNA sequencing with compound heterozygosity for a nonsense/frameshift combination of mutations (p.Arg110X; p.Ala289GlyfsX7) in the FERMT1 gene.

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Nós relatamos uma paciente feminina de 28 anos com Síndrome de Kindler, uma forma rara de Epidermólise Bolhosa. Clinicamente, ela apresentava alterações cutâneas pigmentares disseminadas, fotossensibilidade e fragilidade da pele e das mucosas desde a infância. O envolvimento mucoso levou à estomatite erosiva e a estenoses esofágica, anal e vaginal, as quais necessitaram de intervenções cirúrgicas. O diagnóstico de Síndrome de Kindler foi confirmado por sequenciamento de DNA, que demonstrou heterozigose composta uma combinação de mutações uma nonsense e outra frameshift (p.Arg110X; p.Ala289GlyfsX7) no gene FERMT1.

Assuntos

Adulto , Feminino , Humanos , Vesícula/genética , Códon sem Sentido , Epidermólise Bolhosa/genética , Mutação da Fase de Leitura , Doenças Periodontais/genética , Transtornos de Fotossensibilidade/genética , Vesícula/patologia , Análise Mutacional de DNA , Epidermólise Bolhosa/patologia , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Doenças Periodontais/patologia , Transtornos de Fotossensibilidade/patologia , Pele/patologia

RESUMO

An indeterminate thyroid nodule cytology result occurs about every sixth fine-needle aspiration. These indeterminate nodules harbor a 24% risk of malignancy (ROM); too high to ignore, but driving surgery where most nodules are benign. Molecular diagnostics have emerged to ideally avoid surgery when appropriate, and to trigger the correct therapeutic surgery when indicated, as opposed to an incomplete diagnostic surgery. No current molecular test offers both high sensitivity and high specificity. A molecular diagnostic test with high sensitivity (e.g. Afirma Gene Expression Classifier sensitivity 90%) offers a high Negative Predictive Value when the ROM is relatively low, such as < 30%. Only such tests can "rule-out" cancer. In this setting, a molecularly benign result suggests the same ROM as that of operated cytologically benign nodules (~6%). Thus, clinical observation can replace diagnostic surgery; increasing quality of life and decreasing medical costs. However, its low specificity cannot "rule-in" cancer as a suspicious result has a Positive Predictive Value (PPV) of ~40%, perhaps too low to routinely reflex to definitive cancer surgery. Conversely, high specificity tests (BRAF, RAS, PPAR/PAX-8, RET/PTC, PTEN) offer high PPV results, and only these tests can "rule-in" cancer. Here a positive molecular result warrants definitive therapeutic surgery. However, their low sensitivity cannot "rule-out" cancer and a negative molecular result cannot dissuade diagnostic surgery; limiting their cost-effectiveness. Whether or not there is a useful and cost-effective role to sequentially combine these approaches, or to modify existing approaches, is under investigation.

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Resultados indeterminados na citologia de um nódulo tireoidiano ocorrem em cerca de um a cada seis punções aspirativas por agulha fina. Esses nódulos indeterminados apresentam risco de malignidade (RM) de cerca de 24%, um valor alto demais para ser ignorado e que leva à cirurgia em casos em que a maioria dos nódulos é benigna. O diagnóstico molecular é uma forma ideal de se evitar a cirurgia quando apropriado e de se levar ao correto procedimento cirúrgico terapêutico quando indicado, em oposição à cirurgia diagnóstica incompleta. Atualmente, não existem testes moleculares com alta sensibilidade e especificidade. Um teste molecular de alta sensibilidade (por exemplo, a sensibilidade do teste Afirma Gene Expression Classifier é de 90%) tem um alto Valor Preditivo Negativo quando o RM é relativamente baixo, por exemplo, < 30%. Apenas esses testes podem "excluir" o câncer. Nesse contexto, um resultado molecular benigno sugere o mesmo RM de nódulos com resultado benigno na citologia e operados (~6%). Assim, a observação clínica pode substituir a cirurgia diagnóstica, aumentando a qualidade de vida e diminuindo os custos médicos. Entretanto, a baixa especificidade não pode "incluir" o câncer como um resultado suspeito quando esse resultado tem um Valor Preditivo Positivo (VPP) ~40%, que é talvez baixo demais para levar, rotineiramente, à cirurgia definitiva para o câncer. Por outro lado, testes com alta especificidade (BRAF, RAS, PPAR/PAX-8, RET/PTC, PTEN) têm alto VPP, e apenas esses testes podem "incluir" o câncer. Nesse caso, um resultado molecular positivo leva à recomendação de cirurgia terapêutica definitiva. Entretanto, sua baixa sensibilidade não pode "excluir" o câncer, e um resultado molecular negativo não pode dissuadir o médico de executar a cirurgia diagnóstica, limitando seu custo-benefício. Ainda se investiga se existe ou não um modo útil e com alto custo-benefício de se combinar essas abordagens sequencialmente, ou de se modificar as abordagens existentes.

Assuntos

Humanos , Marcadores Genéticos/genética , Nódulo da Glândula Tireoide/diagnóstico , Biópsia por Agulha Fina , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Nódulo da Glândula Tireoide/genética

RESUMO

OBJECTIVE: The study aimed to investigate gyrA and gyrB mutations in Mycobacterium tuberculosis (MTB) clinical strains from 93 patients with pulmonary tuberculosis in Hubei Province, China, and analyze the association between mutation patterns of the genes and ofloxacin resistance level. RESULTS: Among 93 MTB clinical isolates, 61 were ofloxacin-resistant by the proportion method, and 32 were ofloxacin-susceptible MDR-TB. No mutation in the gyrB gene was found in any MTB strains. In the 61 ofloxacin-resistant isolates, 54 mutations were observed in the gyrA gene. Only one mutation in the gyrA gene was found in ofloxacin-susceptible MDR-TB isolates. In this study, the mutation patterns of gyrA involved seven patterns of single codon mutation (A90V, S91P, S91T, D94N, D94Y, D94G or D94A) and two patterns of double codons mutation (S91P & D94H, S91P & D94A). The ofloxacin minimal inhibitory concentrations (MICs) of three patterns of single codon mutations in the gyrA gene (codons 94, 90 and 91) showed a statistically significant difference (p < 0.0001). CONCLUSIONS: The gyrA mutations at codons 90, 91 and 94 constitute the primary mechanism of fluoroquinolone resistance in MTB, and mutations at codon 91 in the gyrA gene may be associated with low-level resistance to ofloxacin.

Assuntos

Adolescente , Adulto , Feminino , Humanos , Antituberculosos/farmacologia , DNA Girase/genética , Fluoroquinolonas/farmacologia , Mutação/genética , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Pulmonar/microbiologia , China , Farmacorresistência Bacteriana/genética , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Resistente a Múltiplos Medicamentos/genética

RESUMO

Mutações no gene GJB2 constituem a principal causa de surdez genética de herança autossômica recessiva, sendo a mutação 35delG a mais comum em muitos grupos étnicos. Além da mutação 35delG em homozigose, a mutação também é encontrada em heterozigose composta, associada com outras mutações nos genes GJB2 ou GJB6. OBJETIVOS: Determinar a prevalência das mutações 35delG/GJB2 e del (GJB6-D13S1830) em portadores de deficiência auditiva neurossensorial, residentes no estado do Espírito Santo (Brasil). MATERIAL E MÉTODOS: Foram avaliados 77 indivíduos não relacionados, com perda auditiva neurossensorial de moderada a profunda. A mutação 35delG foi estudada através da técnica de PCR/RFLP e a mutação del (GJB6-D13S1830) foi rastreada por meio da técnica de PCR multiplex. RESULTADOS: 88,3 por cento apresentaram genótipo normal para as mutações estudadas, 1,3 por cento foram heterozigotos compostos, 3,9 por cento homozigotos para a mutação 35delG, 6,5 por cento heterozigotos para 35delG/GJB2. A frequência do alelo 35delG/GJB2 e do alelo del (D13S1830/GJB6) na amostra foi de 7,8 por cento e 0,65 por cento, respectivamente. CONCLUSÃO: Os dados obtidos confirmaram a existência das mutações estudadas em casos de perda auditiva neurossensorial na população do Espírito Santo/Brasil. Esses achados reforçam a importância do diagnóstico genético, que pode propiciar um tratamento precoce para crianças e aconselhamento genético para as famílias dos afetados.

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Mutations in GJB2 gene are the leading cause of deafness in autosomal recessive inheritance, and the 35delG mutation is the most common in many ethnic groups. Besides the 35delG mutation in homozygosis, the mutation is also found in compound heterozygosis, coupled with other mutations in genes GJB2 and GJB6. AIM: To determine the prevalence of 35delG/GJB2 and del (GJB6-D13S1830) mutations in patients with sensorineural hearing impairment in residents from the Espirito Santo state, Brazil. MATERIALS AND METHODS: 77 unrelated individuals with moderate to profound sensorineural hearing loss were evaluated. The 35delG mutation was studied by PCR / RFLP; and the del (GJB6-D13S1830) mutation was screened by the technique of multiplex PCR. RESULTS: 88.3 percent had normal genotype for the studied mutations, 1.3 percent were compound heterozygotes, 3.9 percent homozygotic for the 35delG mutation, 6.5 percent heterozygotic for 35delG/GJB2. The frequency of 35delG/GJB2 and del (D13S1830/GJB6) alleles in the sample was 7.8 percent and 0.65 percent, respectively. CONCLUSION: The data confirmed the existence of the mutations studied in cases of sensorineural hearing loss in a population from Espírito Santo / Brazil. These findings reinforce the importance of genetic diagnosis, which can provide early treatment for children and genetic counseling for the affected families.

Assuntos

Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Conexinas/genética , Perda Auditiva Neurossensorial/genética , Mutação/genética , Brasil , Estudos Transversais , Frequência do Gene , Genótipo , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Prevalência , Índice de Gravidade de Doença , Adulto Jovem

RESUMO

OBJECTIVE: The present study aimed at evaluating the PROP1 and HESX1 genes in a group of patients with septo-optic dysplasia (SOD) and pituitary hormone deficiency (combined - CPHD; isolated GH deficiency - GHD). Eleven patients with a clinical and biochemical presentation consistent with CPHD, GHD or SOD were evaluated. SUBJECTS AND METHODS: In all patients, the HESX1 gene was analyzed by direct sequence analysis and in cases of CPHD the PROP1 gene was also sequenced. RESULTS: A polymorphism (1772 A > G; N125S) was identified in a patient with SOD. We found three patients carrying the allelic variants 27 T > C; A9A and 59 A > G; N20S in exon 1 of the PROP1 gene. Mutations in the PROP1 and HESX1 genes were not identified in these patients with sporadic GHD, CPHD and SOD. CONCLUSION: Genetic alterations in one or several other genes, or non-genetic mechanisms, must be implicated in the pathogenic process.

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OBJETIVO: O presente estudo teve como objetivo avaliar os genes PROP1 e HESX1 em um grupo de pacientes com displasia septo-óptica (DSO) e deficiência hormonal hipofisária (combinada - DHHC; ou deficiência isolada de GH - DGH). Onze pacientes com apresentação clínica e bioquímica consistente com DHHC, DGH ou DSO foram avaliados. SUBJECTS AND METHODS: Em todos os pacientes, o gene HESX1 foi analisado pelo sequenciamento direto e, nos casos de DHHC, o gene PROP1 foi também sequenciado. RESULTADOS: Um polimorfismo no gene HESX1 (1772 A > G; N125S) foi identificado em um paciente com DSO. Foram encontrados três pacientes portadores da variação alélica 27 T > C; A9A e 59 A > G; N20S no éxon 1 do gene PROP1. Mutações no gene PROP1 e HESX1 não foram identificadas nesses pacientes com DGH, DHHC e DSO esporádicos. CONCLUSÃO: Alterações genéticas em um ou diversos outros genes ou mecanismos não genéticos devem estar implicados nesse processo patogênico.

Assuntos

Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Proteínas de Homeodomínio/genética , Hormônios Hipofisários/deficiência , Displasia Septo-Óptica/genética , Mutação , Reação em Cadeia da Polimerase , Polimorfismo Genético , Hormônios Hipofisários/genética , Displasia Septo-Óptica/sangue

RESUMO

A acromegalia é doença insidiosa e desfigurante caracterizada por um crescimento desproporcional dos ossos das mãos, pés e do crânio devido à exposição crônica a altos níveis de hormônio de crescimento (GH) e de seu efetor insuline growth factor 1 (IGF-1). Trata-se de uma doença rara, com incidência estimada de 3-4 casos por milhão, com prevalência de aproximadamente 50 casos por milhão de pessoas. A principal causa da acromegalia é a presença de um tumor hipofisário secretor de GH (somatotropinoma). Caso o somatotropinoma ocorra durante a infância ou adolescência, antes do fechamento das epífises dos ossos longos, a criança crescerá longitudinalmente de forma descontrolada, caracterizando a forma clínica gigantismo. Na grande maioria dos casos a acromegalia se apresenta na forma esporádica, entretanto casos familiais da doença podem ocorrer associados à Neoplasia Endócrina Múltipla tipo 1 (NEM-1), ao complexo de Carney (CNC) e à acromegalia familial isolada (IFS). Os genes responsáveis pela NEM-1 (MEN1) e CNC (PRKAR1A) foram clonados há mais 10 anos, entretanto etiologia molecular da IFS permaneceu desconhecida até recentemente. Vierimaa et al. (2006) combinaram estudos de ligação por análise de polimorfismos e estudos de expressão gênica e identificaram mutações no gene AIP em famílias com acromegalia não-NEM-1 e não-CNC; além de perda de heterozigose (LOH) nos somatotropinomas dos pacientes com mutação AIP. No presente estudo, investigamos o gene AIP em três famílias brasileiras com IFS e em seus tumores (hipofisários e não-hipofisários). Descrevemos uma nova mutação AIP (Y268X) em uma família brasileira com IFS, confirmando o papel desse novo gene na predisposição a tumores hipofisários. A partir de dados gerados em uma extensa revisão da literatura, sugerimos que os tumores hipofisários familiais isolados são doenças multigênicas que possuiriam um gene principal, mas que sofreriam influência de outros genes/loci ainda pouco caracterizados...

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Acromegaly is a rare disfigurating and insidious disease characterized by enlargement of hands, feet and skull bones due to excess of growth hormone (GH) secreted by a pituitary tumor (somatotropinoma). The majority of the cases with acromegaly is sporadic, however it may occur in association with inherited disorders as Multiple Endocrine Neoplasia type 1 (MEN1), Carney complex (CNC) and Isolated Familial Somatotropinoma (IFS). The genes associated with MEN1 syndrome (MEN1) and CNC (PRKAR1A) have been described more than a decade ago, however until very recently the molecular etiology of IFS remained unknown. Using a combined strategy of single nucleotide polymorphism (SNP) analysis and gene expression analysis, Vierimaa et al. (2006) described mutations in the AIP gene occurring in families with acromegaly not associated with MEN1 and CNC. In the current study, we investigated three Brazilian families with IFS and were able to describe two germline mutations in the AIP gene, confirming the role of this new gene in the predisposition to familial somatotropinoma. We revised the literature of genetic studies of isolated pituitary adenoma syndromes, which indicated a genetic heterogeneity as well as possible multigenic inheritance for these diseases. Thus, we investigated the role of several genes/loci (SSTR2, SSTR5, CDKN1B, AHR, PRKAR1A, PTTG, PROP1, MEG3, RB1 and 2p16) selected as potentially acting as phenotypic modulators in IFS. Our data indicate that AIP-mutated patients are prone to pituitary disease, however it is necessary the co-segregation of markers located at oncogenic regions to the development of the pituitary tumors and manifestation of the disease. Herein, we also present the first somatic analysis of non-pituitary tumors of AIP-mutated patients. A potential role of AIP, which is implicated in the cAMP pathway, could not be excluded in the development of an adrenocortical carcinoma.

Assuntos

Humanos , Masculino , Feminino , Acromegalia/genética , AMP Cíclico , Genes Supressores de Tumor , Adenoma Hipofisário Secretor de Hormônio do Crescimento , Perda de Heterozigosidade , Neoplasia Endócrina Múltipla/genética

RESUMO

El síndrome X frágil constituye la forma de retraso mental hereditario más frecuente con una incidencia de 1 en 1 500 varones y de 1 en 2 500 hembras; es causado por mutaciones que aumentan el tamaño de un fragmento de ácido desoxinucleótico (DNA) específico en la región Xq 27.3 del cromosoma X. Se presenta el resultado en la introducción y aplicación de la sonda molecular StB12.3 en un grupo control y en miembros afectados de 3 familias. Se exponen las radiografías de los Southern blot que exhiben los patrones diagnósticos posibles a obtener. Esta metodología es mucho más directa, eficiente y confiable para el diagnóstico y prevención de esta forma de retraso mental.

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The fragile X syndrome is the most frequent form of hereditary mental retardation, with an incidence of 1 in 1 500 males, and 1 in 2 500 females; it is caused by mutations that increase the size of a fragment of specific desoxinucleotic acid (DNA) in the Xq 27.3 region of the X chromosome. The outcome in the introduction and application of the StB12.3 molecular probe in a control group and in affected members of three families, is presented. The x-rays of the Southern blot that show the diagnosis patterns possible to obtain, are exposed. This methodology is more direct, effective and reliable for the diagnosis and prevention of this form of mental retardation.