Identification of an elusive spliceogenic MYBPC3 variant in an otherwise genotype-negative hypertrophic cardiomyopathy pedigree.

The finding of a genotype-negative hypertrophic cardiomyopathy (HCM) pedigree with several affected members indicating a familial origin of the disease has driven this study to discover causative gene variants. Genetic testing of the proband and subsequent family screening revealed the presence of a rare variant in the MYBPC3 gene, c.3331-26T>G in intron 30, with evidence supporting cosegregation with the disease in the family. An analysis of potential splice-altering activity using several splicing algorithms consistently yielded low scores. Minigene expression analysis at the mRNA and protein levels revealed that c.3331-26T>G is a spliceogenic variant with major splice-altering activity leading to undetectable levels of properly spliced transcripts or the corresponding protein. Minigene and patient mRNA analyses indicated that this variant induces complete and partial retention of intron 30, which was expected to lead to haploinsufficiency in carrier patients. As most spliceogenic MYBPC3 variants, c.3331-26T>G appears to be non-recurrent, since it was identified in only two additional unrelated probands in our large HCM cohort. In fact, the frequency analysis of 46 known splice-altering MYBPC3 intronic nucleotide substitutions in our HCM cohort revealed 9 recurrent and 16 non-recurrent variants present in a few probands (≤ 4), while 21 were not detected. The identification of non-recurrent elusive MYBPC3 spliceogenic variants that escape detection by in silico algorithms represents a challenge for genetic diagnosis of HCM and contributes to solving a fraction of genotype-negative HCM cases.

Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant.

INTRODUCTION AND OBJECTIVES: TPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees. METHODS: TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain. RESULTS: The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P<.0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ±7.65mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect. CONCLUSIONS: TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.

Importance of Genetic Testing in Dilated Cardiomyopathy: Applications and Challenges in Clinical Practice.

Dilated cardiomyopathy (DCM) is a clinical syndrome characterized by left ventricular dilatation and contractile dysfunction. It is the most common cause of heart failure in young adults. The advent of next-generation sequencing has contributed to the discovery of a large amount of genomic data related to DCM. Mutations involving genes that encode cytoskeletal proteins, the sarcomere, and ion channels account for approximately 40% of cases previously classified as idiopathic DCM. In this scenario, geneticists and cardiovascular genetics specialists have begun to work together, building knowledge and establishing more accurate diagnoses. However, proper interpretation of genetic results is essential and multidisciplinary teams dedicated to the management and analysis of the obtained information should be considered. In this review, we approach genetic factors associated with DCM and their prognostic relevance and discuss how the use of genetic testing, when well recommended, can help cardiologists in the decision-making process.

Importance of Genetic Testing in Dilated Cardiomyopathy: Applications and Challenges in Clinical Practice / Importância do Teste Genético na Miocardiopatia Dilatada: Aplicações e Desafios na Prática Clínica

Abstract Dilated cardiomyopathy (DCM) is a clinical syndrome characterized by left ventricular dilatation and contractile dysfunction. It is the most common cause of heart failure in young adults. The advent of next-generation sequencing has contributed to the discovery of a large amount of genomic data related to DCM. Mutations involving genes that encode cytoskeletal proteins, the sarcomere, and ion channels account for approximately 40% of cases previously classified as idiopathic DCM. In this scenario, geneticists and cardiovascular genetics specialists have begun to work together, building knowledge and establishing more accurate diagnoses. However, proper interpretation of genetic results is essential and multidisciplinary teams dedicated to the management and analysis of the obtained information should be considered. In this review, we approach genetic factors associated with DCM and their prognostic relevance and discuss how the use of genetic testing, when well recommended, can help cardiologists in the decision-making process.

Resumo A miocardiopatia dilatada (MCD) é uma síndrome caracterizada por dilatação ventricular esquerda e disfunção contrátil, sendo considerada a causa mais comum de insuficiência cardíaca em adultos jovens. O uso do sequenciamento de nova geração tem contribuído com a descoberta de uma grande quantidade de dados genômicos relacionados à MCD, identificando mutações que envolvem genes que codificam proteínas do citoesqueleto, sarcômero e canais iônicos, os quais são responsáveis por aproximadamente 40% dos casos classificados como MCD idiopática. Nesse cenário, geneticistas e especialistas em genética cardiovascular passaram a atuar em conjunto, agregando conhecimento e estabelecendo diagnósticos mais precisos. No entanto, é fundamental interpretar corretamente os resultados genéticos, sendo necessário criar e fomentar equipes multidisciplinares dedicadas à gestão e análise das informações coletadas. Nesta revisão, abordamos os fatores genéticos associados à MCD, aspectos prognósticos, além de discutirmos como o emprego dos testes genéticos, quando bem indicados, pode ser útil na tomada de decisão na prática clínica dos cardiologistas.

Agricultura familiar e saúde em zona rural: um estudo de caso sobre vulnerabilidade socioambiental no Município de Frei Inocêncio, Médio Rio Doce, Minas Gerais / Family agriculture and health in rural areas: a case study on environmental vulnerability in the municipality of Frei Innocent, Middle Rio Doce, Minas Gerais

O presente projeto analisou, de forma exploratória, a relação entre agricultura familiar e saúde no município de Frei Inocêncio, região do Médio Vale do Rio Doce, MG. Considerando as particularidades territoriais do processo saúde-doença em cada localidade, procuramos conhecer a constituição histórica do Médio Rio Doce, com ênfase nos determinantes sociais em saúde e nas descrições das condições de vida dos agricultores tradicionais. A proposta foi desenvolver, de forma mais específica, a construção de índices de vulnerabilidade socioambiental e de saúde no município e compará-los dentre a totalidade dos municípios do Estado de Minas Gerais. O objetivo desta comparação é estabelecer um índice de vulnerabilidade socioambiental que permita verificar a situação da agricultura familiar e suas repercussões para a saúde em zona rural. Para tanto foram utilizadas diversas fontes secundárias, como os registros administrativos (SINAN e SIAB) do DATASUS e o Censo Agropecuário de 2006/IBGE. Pautada no marco da Justiça Ambiental, a parte final deste estudo apresentou para os atores sociais locais envolvidos na temática em questão os resultados obtidos nas etapas anteriores, incorporando assim o seu saber territorial como princípio ético da análise e estimulando possibilidades de debate sobre o tema da agricultura familiar, desenvolvimento social rural e saúde na região.