Prevalence and Phenotypic Expression of Mutations in the MYH7, MYBPC3 and TNNT2 Genes in Families with Hypertrophic Cardiomyopathy in the South of Brazil: A Cross-Sectional Study

Abstract

Background:Mutations in sarcomeric genes are found in 60-70% of individuals with familial forms of hypertrophic cardiomyopathy (HCM). However, this estimate refers to northern hemisphere populations. The molecular-genetic profile of HCM has been subject of few investigations in Brazil, particularly in the south of the country.Objective:To investigate mutations in the sarcomeric genes MYH7, MYBPC3 and TNNT2 in a cohort of HCM patients living in the extreme south of Brazil, and to evaluate genotype-phenotype associations.Methods:Direct DNA sequencing of all encoding regions of three sarcomeric genes was conducted in 43 consecutive individuals of ten unrelated families.Results:Mutations for CMH have been found in 25 (58%) patients of seven (70%) of the ten study families. Fourteen (56%) individuals were phenotype-positive. All mutations were missense, four (66%) in MYH7 and two (33%) in MYBPC3. We have not found mutations in the TNNT2 gene. Mutations in MYH7 were identified in 20 (47%) patients of six (60%) families. Two of them had not been previously described. Mutations in MYBPC3 were found in seven (16%) members of two (20%) families. Two (5%) patients showed double heterozygosis for both genes. The mutations affected different domains of encoded proteins and led to variable phenotypic expression. A family history of HCM was identified in all genotype-positive individuals.Conclusions:In this first genetic-molecular analysis carried out in the south of Brazil, we found mutations in the sarcomeric genes MYH7 and MYBPC3 in 58% of individuals. MYH7-related disease was identified in the majority of cases with mutation.

Sarcomeric Gene Variants and Their Role with Left Ventricular Dysfunction in Background of Coronary Artery Disease

“…Several genetic studies have found an association between LVD and dilated cardiomyopathy (DCM). Various sarcomeric protein-encoding genes such as cardiac myosin-binding protein C (MYBPC3), myosin heavy polypeptide, and cardiac troponin I gene mutations, as well as other gene mutations have been identified in DCM [7][8][9][10][11][12][13]. The common sarcomeric gene polymorphisms with their locations and functional roles are given in Table 1.…”

“…Mutations in the TNNT2 gene have been positively associated with DCM and familial HCM [20,74,75]. It has been reported that a 5-bp (CTTCT) I/ D polymorphism present in intron 3 of the TNNT2 gene may impair the skipping of exon 4 and lead to LVD [10,19,20].…”

Myosin-binding Protein C Compound Heterozygous Variant Effect on the Phenotypic Expression of Hypertrophic Cardiomyopathy

“…The constructed heredogram revealed 30 relatives, over five generations, in which only one unexplained death of a 30-year-old female with no HCM diagnosis was detected ( Figure 2 ). 14 …”

“…However, several other genes have already been associated to this disease 5,14 , which are yet to be investigated.…”

Discordância entre Diretrizes Internacionais sobre Critérios de Prevenção Primária de Morte Súbita na Cardiomiopatia Hipertrófica

“…Molecular-genetic testing was performed in 18 (20%) patients, whose results were previously published. 18 Diagnosis was established according to the current guidelines 15,17 based on the identification of unexplained LV hypertrophy detected on echocardiogram and/or magnetic resonance imaging by the presence of MLVWT ≥15 mm measured at any segment, with septum/ posterior wall ratio ≥1.3 in the absence of chamber dilation or other conditions capable of producing a similar pattern of hypertrophy. Eighteen cases were excluded due to a follow-up period <12 months or previous history of cardiopulmonary arrest, ventricular fibrillation or ventricular tachycardia with hemodynamic impairment.…”