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PURPOSE: To define the spectrum of germline pathogenic variants (PVs) and copy number variant (CNV) in cancer susceptibility genes to the burden of breast and ovarian cancer (BC, OvC) in high-risk Brazilians in Minas Gerais with health insurance, southeast Brazil, undergoing multigene panel testing (MGPT). METHODS: Genotyping eligible individuals with health insurance in the Brazilian healthcare system for Hereditary Breast and Ovarian Cancer Syndrome to undergo molecular testing for 44 or 141-gene panels, a decision that was insurance driven. RESULTS: Overall, 701 individuals clinically defined as high BC/OvC risk, underwent MGPT from 1/2021 to 10/2022, with ~ 50% genotyped with a 44-gene panel and the rest with a 141-gene panel. Overall, 16.4% and 22.6% of genotyped individuals harbored PVs using 44-gene and the 141 gene panel, respectively. The most frequently mutated genes were: BRCA2 (3.7%); BRCA1 (3.6%) and monoallelic MUTYH (3.1%). CONCLUSION: The rate of PVs detected in high-risk individuals in this study was twice the 10% threshold used in Brazilian health guidelines. MGPT doubled the detection rate of PVs in cancer susceptibility genes in high-risk individuals compared with BRCA1/BRCA2 genotyping alone. The spectrum of PVs in Southern Brazil is diverse, with few recurring variants such as TP53 (0.6%), suggesting regional founder effects. The use of MGPT in hereditary cancer in Minas Gerais significantly increased the detection rate of P/LPVs compared to existing guidelines and should be considered as the primary genotyping modality in assessing hereditary cancer risk in Brazil.
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BACKGROUND: The Congenital Adrenal Hyperplasia due to 21 hydroxylase deficiency is the most common cause of genital ambiguity in persons with XX sexual chromosomes. Genital ambiguity among persons with XY sexual chromosomes comprises diverse and rare etiologies. The deficiency of 17-beta-hydroxysteroid dehydrogenase type 3 enzyme (HSD17B3) is a rare autosomal recessive disorder due to functionally altered variants of the HSD17B3 gene. In this disorder/difference of sex development, the conversion of androstenedione into testosterone is impaired. The appearance of external genitalia of 46,XY individuals varies from typically male to almost female. CASE PRESENTATION: We report on a child presenting severe ambiguous genitalia. Due to access constraints, specialized care did not start until the child was 10 months old. Parents are consanguineous and were born in an area of high isonymy that is a cluster for rare recessive diseases. A new homozygous missense variant c.785G > T was found in exon 10 of the HSD17B3 gene. CONCLUSIONS: Researchers-clinicians and researchers-researchers collaborative efforts to elucidate the genetic basis of this disease were critical since this etiologic investigation is not available through the public health system. This case exemplifies the families' pilgrimage in cases of genital ambiguity due to a rare genetic condition. Recognizing the etiology was the baseline to provide information on prognosis and treatment options, and to shelter family and child doubts and hopes in order to better support their decisions.
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Hiperplasia Suprarrenal Congênita , Transtornos do Desenvolvimento Sexual , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Criança , Consanguinidade , Éxons , Feminino , Humanos , Lactente , Masculino , Mutação de Sentido IncorretoRESUMO
Abstract Objectives: the present study aimed to evaluate the association between the rs1799998 polymorphism of the CYP11B2 gene and the susceptibility to preeclampsia (PE) in a Brazilian population. Methods: the study group comprised 61 women who were diagnosed with PE. The control group included 116 women who did not show changes in their blood pressure levels during their pregnancies. The rs1799998 polymorphism of the CYP11B2 gene was amplified by allele-specific polymerase chain reaction (PCR). A multiple logistic regression analysis was performed using the SNPStat program to evaluate the risk of the CYP11B2 gene rs1799998 polymorphism contributing to PE. Results: the PE group had the following genotypes: 1.64% CC, 91.80% CT, and 6.56% TT. In the control group, the observed genotypic frequencies were: 11% CC, 73% CT, and 16% TT. The genotypic frequency distribution did not fit the Hardy Weinberg Equilibrium (HWE) in either study group. The multiple logistic regression analysis showed a statistically significant difference for the rs1799998 polymorphism in the recessive model. Conclusion: the results suggest an association between the recessive model of C/C genotype of the rs1799998 polymorphism of the CYP11B2 gene and susceptibility to PE.
Resumo Objetivos: avaliar a associação entre o polimorfismo rs1799998 do gene CYP11B2 e a suscetibilidade à PE em uma população brasileira. Métodos: participaram desse estudo 61 mulheres com PE e 116 mulheres normotensas. O polimorfismo rs1799998 do gene CYP11B2 foi amplificado por PCR alelo-específica. O risco do polimorfismo rs1799998 do gene CYP11B2 contribuir com a PE foi avaliado pela análise de regressão logística múltipla. Resultados: as frequências genotípicas observadas foram 1.64% CC, 91.80% CT e 6.56% TT no grupo PE e 11%CC, 73%CT e 16%TT grupo controle. A distribuição da frequência genotípica não estava em Equilíbrio de Hardy Weinberg em nenhum dos grupos estudados. A análise de regressão logística múltipla demonstrou diferença estatisticamente significativa para o polimorfismo rs1799998 no modelo recessivo. Conclusão: o presente trabalho sugere associação do genótipo C/C no modelo recessivo, do polimorfismo rs1799998 do gene CYP11B2 com a suscetibilidade a PE.
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Humanos , Feminino , Gravidez , Polimorfismo Genético , Pré-Eclâmpsia/genética , Citocromo P-450 CYP11B2 , Sistema Enzimático do Citocromo P-450 , Brasil , Marcadores Genéticos , Modelos Logísticos , Predisposição Genética para Doença , Perfil GenéticoRESUMO
INTRODUCTION: Pre-eclampsia (PE) is a pregnancy-specific multisystemic syndrome characterized by high blood pressure and presence of protein in the urine. The pathogenesis of pre-eclampsia is poorly understood and many factors such as environment, genetic, and immunology may be involved in PE pathophysiology. Among the genetic factors, there is an association between pre-eclampsia and polymorphisms in some genes of different population samples, as vascular endothelial growth factor and interleukin 1 alpha. The vascular endothelial growth factor gene is highly polymorphic and acts as a regulator in endothelial cell proliferation and vascular permeability. The secretion of interleukin 1 alpha leads to a pro-inflammatory cascade, which leads to high levels of circulating cytokines. This high amount of cytokines corroborates to structural and functional alterations in endothelial cells. The aim of this study was to investigate the vascular endothelial growth factor (VEGF) G-634C and interleukin 1 alpha (IL1A) rs3783550 polymorphism in a specific Brazilian pre-eclampsia group. MATERIAL AND METHODS: The evaluation of the vascular endothelial growth factor polymorphism was performed by PCR-RFLP restriction enzyme BsmFI and the IL1A polymorphism by allele-specific PCR. Molecular investigation was carried out by fragment size analysis on agarose and/or polyacrylamide gels. RESULTS: However, no relation between polymorphism VEGF G-634C and pre-eclampsia was observed, indicating that further investigations with a larger sampling and other polymorphisms are still required. On the other hand, the rs3783550 polymorphism in the interleukin 1 alpha gene is correlated to pre-eclampsia, indicating that women with the allele A have a higher probability of developing the disease. CONCLUSION: Thus, the interleukin 1 alpha gene could be used as a therapeutic tool for the diagnosis, as well as for monitoring the patients.
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Interleucina-1alfa/genética , Polimorfismo de Fragmento de Restrição , Pré-Eclâmpsia/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Alelos , Brasil , Feminino , Humanos , Pré-Eclâmpsia/metabolismo , GravidezRESUMO
Mutations in the myocilin gene (MYOC) account for most cases of autosomal dominant juvenile-onset open-angle glaucoma (JOAG), an earlier and more severe form of POAG. We accessed seven members of a Brazilian JOAG family by clinical and molecular investigation. Four out of seven family members were diagnosed with JOAG. All of these patients presented high intraocular pressure and two of them were bilaterally blind. The disease onset varied from 20 to 30years old. There was a nine-year-old family member who had not yet manifested the disease, although he was also a carrier of the mutation. Ophthalmologic examination included: evaluation of the visual field and optic disc, intraocular pressure measurement, and gonioscopy. The three exons and intron/exon junctions of the MYOC gene were screened for mutations through direct sequencing of PCR-amplified DNA fragments. Mutation screening revealed an in-frame mutation in the third exon of the MYOC gene: an insertion of six nucleotides between the cDNA positions 1187 and 1188 (c.1187_1188insCCCAGA, p.D395_E396insDP). This mutation presented an autosomal dominant pattern of inheritance, segregating with the disease in four family members for three generations, and it was absent in 60 normal controls. We also performed a computational structure modeling of olfactomedin-like domain of myocilin protein and conducted in silico analysis to predict the structural changes in the myocilin protein due to the presence of the mutation. These findings may be important for future diagnosis of other presymptomatic family members, as well as for the increase of the panel of MYOC mutations and their effects on phenotype.
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Proteínas do Citoesqueleto/genética , Proteínas do Olho/genética , Glaucoma de Ângulo Aberto/genética , Glicoproteínas/genética , Mutação , Adulto , Idade de Início , Idoso , Sequência de Aminoácidos , Brasil , Biologia Computacional , Análise Mutacional de DNA , Éxons , Feminino , Predisposição Genética para Doença , Testes Genéticos , Glaucoma de Ângulo Aberto/diagnóstico , Gonioscopia , Humanos , Pressão Intraocular/genética , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Oftalmologia , Disco Óptico/patologia , Linhagem , Fenótipo , Estrutura Terciária de Proteína , Campos Visuais/genética , Adulto JovemRESUMO
Frasier syndrome (FS) is characterized by gonadal dysgenesis and nephropathy. It is caused by specific mutations in the Wilms' tumor suppressor gene (WT1) located in 11p23. Patients with the 46,XY karyotype present normal female genitalia with streak gonads, and have higher risk of gonadal tumor, mainly, gonadoblastoma. Therefore, elective bilateral gonadectomy is indicated. Nephropathy in FS consists in nephrotic syndrome (NS) with proteinuria that begins early in childhood and progressively increases with age, mainly due to nonspecific focal and segmental glomerular sclerosis (FSGS). Patients are generally unresponsive to steroid and immunosuppressive therapies, and will develop end-stage renal failure (ESRF) during the second or third decade of life. We report here four cases of FS diagnosis after identification of WT1 mutations. Case 1 was part of a large cohort of patients diagnosed with steroid-resistant nephrotic syndrome, in whom the screening for mutations within WT1 8-9 hotspot fragment identified the IVS9+5G>A mutation. Beside FS, this patient showed unusual characteristics, such as urinary malformation (horseshoe kidney), and bilateral dysgerminoma. Cases 2 and 3, also bearing the IVS9+5G>A mutation, and case 4, with IVS9+1G>A mutation, were studied due to FSGS and/or delayed puberty; additionally, patients 2 and 4 developed bilateral gonadal tumors. Since the great majority of FS patients have normal female external genitalia, sex reversal is not suspected before they present delayed puberty and/or primary amenorrhea. Therefore, molecular screening of WT1 gene is very important to confirm the FS diagnosis. Arq Bras Endocrinol Metab. 2012;56(8):525-32.
A síndrome de Frasier (SF), caracterizada por disgenesia gonadal e nefropatia, é causada por mutações específicas no gene supressor do tumor de Wilms (WT1) localizado em 11p23. Pacientes com cariótipo 46,XY apresentam genitália feminina normal com gônadas disgenéticas e alto risco de tumor gonadal, principalmente o gonadoblastoma. Por isso, a gonadectomia bilateral eletiva está indicada. A nefropatia na SF consiste de síndrome nefrótica com proteinúria que se inicia na infância e aumenta progressivamente com a idade, principalmente devido à glomeruloesclerose focal e segmentar (GESF). Esses pacientes não respondem ao tratamento com esteroides e imunossupressores e desenvolverão insuficiência renal crônica durante a segunda ou terceira década de vida. Neste trabalho, são relatados quatro casos de SF cujo diagnóstico foi definido após o rastreamento molecular do gene WT1. O caso 1 faz parte de um grande grupo de pacientes que tiveram diagnóstico de síndrome nefrótica corticorresistente e no qual o rastreamento de mutações no fragmento 8-9 do gene WT1 identificou a mutação IVS9+5G>A. Além da SF, essa paciente apresentou características incomuns, tais como malformação urinária (rins em ferradura) e disgerminoma bilateral. Os casos 2 e 3 também apresentaram a mutação IVS9+5G>A, e, no caso 4, foi identificada a mutação IVS9+1G>A, sendo que esses três casos foram encaminhados para estudo molecular em decorrência de GESF e/ou atraso no desenvolvimento puberal. Além disso, as pacientes 2 e 4 desenvolveram tumor gonadal bilateral. Visto que a maioria dos pacientes com SF apresenta genitália externa feminina, não há suspeita de sexo reverso até apresentarem atraso puberal e/ou amenorreia primária. Portanto, o rastreamento molecular do gene WT1 é de fundamental importância para se confirmar o diagnóstico de SF. Arq Bras Endocrinol Metab. 2012;56(8):525-32.
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Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Síndrome de Frasier/genética , Mutação/genética , Proteínas WT1/genética , Síndrome de Frasier/diagnóstico , Gonadoblastoma/genética , Neoplasias Ovarianas/genéticaRESUMO
Frasier syndrome (FS) is characterized by gonadal dysgenesis and nephropathy. It is caused by specific mutations in the Wilms' tumor suppressor gene (WT1) located in 11p23. Patients with the 46,XY karyotype present normal female genitalia with streak gonads, and have higher risk of gonadal tumor, mainly, gonadoblastoma. Therefore, elective bilateral gonadectomy is indicated. Nephropathy in FS consists in nephrotic syndrome (NS) with proteinuria that begins early in childhood and progressively increases with age, mainly due to nonspecific focal and segmental glomerular sclerosis (FSGS). Patients are generally unresponsive to steroid and immunosuppressive therapies, and will develop end-stage renal failure (ESRF) during the second or third decade of life. We report here four cases of FS diagnosis after identification of WT1 mutations. Case 1 was part of a large cohort of patients diagnosed with steroid-resistant nephrotic syndrome, in whom the screening for mutations within WT1 8-9 hotspot fragment identified the IVS9+5G>A mutation. Beside FS, this patient showed unusual characteristics, such as urinary malformation (horseshoe kidney), and bilateral dysgerminoma. Cases 2 and 3, also bearing the IVS9+5G>A mutation, and case 4, with IVS9+1G>A mutation, were studied due to FSGS and/or delayed puberty; additionally, patients 2 and 4 developed bilateral gonadal tumors. Since the great majority of FS patients have normal female external genitalia, sex reversal is not suspected before they present delayed puberty and/or primary amenorrhea. Therefore, molecular screening of WT1 gene is very important to confirm the FS diagnosis.
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Síndrome de Frasier/genética , Mutação/genética , Proteínas WT1/genética , Adolescente , Criança , Pré-Escolar , Feminino , Síndrome de Frasier/diagnóstico , Gonadoblastoma/genética , Humanos , Neoplasias Ovarianas/genéticaRESUMO
The steroid 5α-reductase type II enzyme catalyzes the conversion of testosterone (T) to dihydrotestosterone (DHT), and its deficiency leads to undervirilization in 46,XY individuals, due to an impairment of this conversion in genital tissues. Molecular analysis in the steroid 5α-reductase type II gene (SRD5A2) was performed in two 46,XY female siblings. SRD5A2 gene sequencing revealed that the patients were homozygous for p.Gln126Arg missense mutation, which results from the CGA > CAA nucleotide substitution. The molecular result confirmed clinical diagnosis of 46,XY disorder of sex development (DSD) for the older sister and directed the investigation to other family members. Studies on SRD5A2 protein structure showed severe changes at NADPH binding region indicating that structural modeling analysis can be useful to evaluate the deleterious role of a mutation as causing 5α-reductase type II enzyme deficiency.
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3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Transtorno 46,XY do Desenvolvimento Sexual/genética , Proteínas de Membrana/genética , Mutação de Sentido Incorreto , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/química , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Adolescente , Sequência de Aminoácidos , Sítios de Ligação , Brasil , Criança , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Feminino , Homozigoto , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Dados de Sequência Molecular , LinhagemRESUMO
X-linked adrenoleukodystrophy (X-ALD) is an inherited disease with clinical heterogeneity varying from presymptomatic individuals to rapidly progressive cerebral ALD forms. This disease is characterized by increased concentration of very long chain fatty acids (VLCFAs) in plasma and in adrenal, testicular and nervous tissues. Affected individuals can be classified in different clinical settings, according to phenotypic expression and age at onset of initial symptoms. Molecular defects in X-ALD individuals usually result from ABCD1 gene mutations. In the present report we describe clinical data and the ABCD1 gene study in two boys affected with the childhood cerebral form that presented with different symptomatic manifestations at diagnosis. In addition, their maternal grandfather had been diagnosed with Addison's disease indicating phenotypic variation for X-ALD within this family. The mutation p.Trp132Ter was identified in both male patients; additionally, three females, out of eleven family members, were found to be heterozygous after screening for this mutation. In the present report, the molecular analysis was especially important since one of the heterozygous females was in first stages of pregnancy. Therefore, depending on the fetus outcome, if male and p.Trp132Ter carrier, storage of the umbilical cord blood should be recommended as hematopoietic stem cell transplantation could be considered as an option for treatment in the future.
A adrenoleucodistrofia é uma doença genética com padrão de herança ligado ao X (X-ALD) que apresenta heterogeneidade clínica e varia desde a forma infantil cerebral severa até casos de indivíduos pré-sintomáticos. Essa doença é caracterizada pelo acúmulo de ácidos graxos de cadeia muito longa (VLCFA) no plasma, nas adrenais, nos testículos e no sistema nervoso. Indivíduos afetados podem apresentar diferentes formas clínicas, as quais são classificadas de acordo com a expressão fenotípica e a idade de aparecimento dos sintomas iniciais. Alterações moleculares em indivíduos com X-ALD são geralmente mutações no gene ABCD1. No presente trabalho, descrevemos os dados clínicos e a investigação molecular do gene ABCD1 em uma família com duas crianças do sexo masculino afetadas com a forma infantil cerebral, que apresentaram diferenças nas primeiras manifestações sintomáticas para o diagnóstico. Além disso, houve referência ao avô materno diagnosticado com doença de Addison's, indicando a variabilidade fenotípica da X-ALD nessa família. A análise molecular indicou a mutação p.Trp132Ter nos dois pacientes masculinos, e três indivíduos do sexo feminino, entre os onze estudados, mostraram-se heterozigotos para mutação. O conhecimento molecular descrito no presente relato adquiriu maior importância uma vez que uma das portadoras da mutação apresentou-se nos primeiros estágios de gestação. Assim, poderá ser oferecida a possibilidade de armazenamento de sangue de cordão umbilical para que se possa considerar, no futuro, o transplante de células-tronco hematopoiéticas como forma de tratamento, caso a criança seja do sexo masculino e afetada.
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Criança , Feminino , Humanos , Masculino , Gravidez , Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/genética , Linhagem , Fenótipo , Mutação/genética , Análise de Sequência de DNARESUMO
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary cancer syndrome characterized mostly by parathyroid, enteropancreatic, and anterior pituitary tumors. We present a case of an 8-year-old boy referred because of hypoglycemic attacks. His diagnosis was pancreatic insulinoma. Paternal grandmother died due to repeated gastroduodenal ulcerations and a paternal aunt presented similar manifestations. At a first evaluation, the father presented only gastric ulceration but subsequently developed hyperparathyroidism and lung carcinoid tumor. During almost 15 years of follow-up, three brothers and the index case presented hyperparathyroidism and hyperprolactinemia. Molecular study showed a G to A substitution in intron 4, at nine nucleotides upstream of the splicing acceptor site, causing a splicing mutation. All affected members of the family have the same mutation. Paternal grandmother and aunt were not studied and the mother does not carry any mutation. MEN1 is a rare condition that requires permanent medical assistance. Early clinical and genetic identification of affected individuals is essential for their own surveillance and also for genetic counseling.
A neoplasia endócrina múltipla tipo 1 (NEM1) é uma doença hereditária autossômica dominante, caracterizada principalmente por tumores de paratireoide, enteropancreáticos e adeno-hipofisários. Apresentamos o caso de um menino com 8 anos encaminhado por crises de hipoglicemia. Seu diagnóstico foi insulinoma pancreático. Sua avó paterna faleceu por úlceras gastroduodenais de repetição e a tia paterna tinha as mesmas manifestações. Na primeira avaliação, o pai apresentou apenas úlcera gástrica, porém com a evolução desenvolveu hiperparatireoidismo e tumor carcinoide pulmonar. Durante cerca de 15 anos de seguimento, os três irmãos e o caso índice desenvolveram hiperparatireoidismo e hiperprolactinemia. O estudo molecular mostrou a substituição G por A no intron 4, a nove nucleotídeos do sítio aceptor de splicing, criando um novo sítio de splicing. Todos os membros da família afetados e estudados tinham a mesma mutação. A NEM1 é uma condição rara que requer assistência médica permanente. As identificações clínicas e genéticas precoces são essenciais para o tratamento e aconselhamento genético.