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The authors report the clinical and genetic investigation of a family with hypertrophic cardiomyopathy (HCM). The individuals described are three affected first-degree relatives (father, daughter and son), one affected niece and unaffected nephew and niece. Those affected all share a very similar phenotype consisting of asymmetric HCM, with hypertrophy particularly affecting the septum and the anterior wall, and similar electrocardiographic features, including a short PR interval. Case 1 (proband) presented with obstructive HCM and had undergone myectomy and mitral valve replacement. Case 2 (oldest offspring of Case 1) had non-obstructive HCM with exertional angina and NYHA II heart failure (HF) symptoms; she developed non-sustained ventricular tachycardia during follow-up and received a single-chamber ICD for primary prevention of sudden cardiac death. Case 3 (son of case 1) presented with asymptomatic non-obstructive HCM and developed NYHA II HF symptoms during follow-up. Case 4 had non-obstructive HCM, mainly with NYHA II HF symptoms. Testing of the proband for sarcomeric mutations and phenocopies was initially negative. After eight years of clinical follow-up, the suspicion of an undiscovered pathogenic gene mutation shared among the members of this family led us to enroll the proband in a whole-genome sequencing research project, which revealed a heterozygous pathogenic intronic MYBPC3 variant (c.1227-13G>A [rs397515893]), cosegregating with the phenotype., (Copyright © 2020 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the alpha galactosidase A gene (GLA) that lead to the enzymatic deficiency of alpha galactosidase (α-Gal A), resulting in the accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), causing multiple organ dysfunctions., Objective: To perform GLA gene screening in a group of patients with echocardiographic diagnosis of hypertrophic cardiomyopathy (HCM)., Methods: a cross-sectional study was conducted with HCM patients from a university hospital. Patients with coronary artery disease and valvulopathies were excluded. Mutation analysis of the GLA gene was performed. In male subjects, the analysis was performed after evidence of low α-Gal A activity., Results: 60 patients with echocardiographic diagnosis of HCM were included. Age ranged from 12 to 85 years and 60% were women. Mean myocardial fibrosis percentage on MRI was 10.7 ± 13.1% and mean ventricular thickness was18.7 ± 6.7 mm. Four patients had the following GLA gene mutations: c.967C>A (p.Pro323Thr), not yet described in the literature; c.937G>T (p.Asp313Tyr); and c.352C>T (p.Arg118Cys). All patients had normal levels of lyso-Gb3 and non-ischemic myocardial fibrosis on magnetic resonance imaging; one patient had proteinuria and one patient had ventricular tachycardia., Conclusion: in this study, the frequency of mutation in the GLA gene in patients with HCM was 6.7%. A novel mutation in exon 6 of the GLA gene, c.967C>A (p.Pro323Thr), was identified. Patients with HCM may have GLA mutations and FD should be ruled out. Plasma (lyso-Gb3) levels do not seem to be sufficient to attain a diagnosis and organ biopsy should be considered.

The lamin A/C (LMNA) gene encodes lamins A and C, which have an important role in nuclear cohesion and chromatin organization. Mutations in this gene usually lead to the so-called laminopathies, the primary cardiac manifestations of which are dilated cardiomyopathy and intracardiac conduction defects. Some mutations, associated with lipodystrophy but not cardiomyopathy, have been linked to metabolic abnormalities such as diabetes and severe dyslipidemia. Herein we describe a new phenotype associated with a mutation in exon 11 of the LMNA gene: hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes. A 64-year-old woman with hypertrophic cardiomyopathy and a point mutation in exon 11 of the LMNA gene (c.1718C>T, Ser573Leu) presented with severe symptomatic ventricular hypertrophy and left ventricular outflow tract obstruction. She underwent septal alcohol ablation, followed by Morrow myectomy. The patient was also diagnosed with severe dyslipidemia, diabetes and obesity, and fulfilled diagnostic criteria for metabolic syndrome. No other characteristics of LMNA mutation-related phenotypes were identified. The development of type III atrioventricular block with no apparent cause, and mildly depressed systolic function, prompted referral for cardiac resynchronization therapy. In conclusion, the association between LMNA mutations and different phenotypes is complex and not fully understood, and can present with a broad spectrum of severity., (Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disease caused by mutations in genes encoding sarcomere proteins. It is the major cause of sudden cardiac death in young high-level athletes. Studies have demonstrated a poorer prognosis when associated with specific mutations. The association between HCM genotype and phenotype has been the subject of several studies since the discovery of the genetic nature of the disease. This study shows the effect of a MYBPC3 compound variant on the phenotypic HCM expression. A family in which a young man had a clinical diagnosis of HCM underwent clinical and genetic investigations. The coding regions of the MYH7, MYBPC3 and TNNT2 genes were sequenced and analyzed. The proband present a malignant manifestation of the disease, and is the only one to express HCM in his family. The genetic analysis through direct sequencing of the three main genes related to this disease identified a compound heterozygous variant (p.E542Q and p.D610H) in MYBPC3. A family analysis indicated that the p.E542Q and p.D610H alleles have paternal and maternal origin, respectively. No family member carrier of one of the variant alleles manifested clinical signs of HCM. We suggest that the MYBPC3-biallelic heterozygous expression of p.E542Q and p.D610H may cause the severe disease phenotype seen in the proband. Resumo A cardiomiopatia hipertrófica (CMH) é uma doença autossômica dominante causada por mutações em genes que codificam as proteínas dos sarcômeros. É a principal causa de morte súbita cardíaca em atletas jovens de alto nível. Estudos têm demonstrado um pior prognóstico associado a mutações específicas. A associação entre genótipo e fenótipo em CMH tem sido objeto de diversos estudos desde a descoberta da origem genética dessa doença. Este trabalho apresenta o efeito de uma mutação composta em MYBPC3 na expressão fenotípica da CMH. Uma família na qual um jovem tem o diagnóstico clínico de CMH foi submetida à investigação clínica e genética. As regiões codificadoras dos genes MYH7, MYBPC3 e TNNT2 foram sequenciadas e analisadas. O probando apresenta uma manifestação maligna da doença e é o único em sua família a desenvolver CMH. A análise genética pelo sequenciamento direto dos três principais genes relacionados à essa doença identificou uma variante em heterozigose composta (p.E542Q e p.D610H) em MYBPC3. A análise da família mostrou que os alelos p.E542Q e p.D610H tem origem paterna e materna, respectivamente. Nenhum familiar portador de um dos alelos variantes manifestou sinais clínicos de CMH. Sugerimos que a expressão heterozigótica bialélica de p.E542Q e p.D610H pode ser responsável pelo fenótipo severo da doença encontrada no probando.

Introduction and Aim: The prognostic value of late gadolinium enhancement (LGE) for risk stratification of hypertrophic cardiomyopathy (HCM) patients is the subject of disagreement. We set out to examine the association between clinical and morphological variables, risk factors for sudden cardiac death and LGE in HCM patients., Methods: From a population of 78 patients with HCM, we studied 53 who underwent cardiac magnetic resonance. They were divided into two groups according to the presence or absence of LGE. Ventricular arrhythmias and morbidity and mortality during follow-up were analyzed., Results: Patients with LGE were younger at the time of diagnosis (p=0.046) and more often had a family history of sudden death (p=0.008) and known coronary artery disease (p=0.086). On echocardiography they had greater maximum wall thickness (p=0.007) and left atrial area (p=0.037) and volume (p=0.035), and more often presented a restrictive pattern of diastolic dysfunction (p=0.011) with a higher E/É ratio (p=0.003) and left ventricular systolic dysfunction (p=0.038). Cardiac magnetic resonance supported the association between LGE and previous echocardiographic findings: greater left atrial area (p=0.029) and maximum wall thickness (p<0.001) and lower left ventricular ejection fraction (p=0.056). Patients with LGE more often had an implantable cardioverter-defibrillator (ICD) (p=0.015). At follow-up, no differences were found in the frequency of ventricular arrhythmias, appropriate ICD therapies or mortality., Conclusions: The presence of LGE emerges as a risk marker, associated with the classical predictors of sudden cardiac death in this population. However, larger studies are required to confirm its independent association with clinical events., (Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) is the most common monogenic genetic cardiac disease, with an estimated prevalence of 1:500 in the general population. Clinically, HCM is characterized by hypertrophy of the left ventricle (LV) walls, especially the septum, usually asymmetric, in the absence of any cardiac or systemic disease that leads to a secondary hypertrophy. The clinical course of the disease has a large inter- and intrafamilial heterogeneity, ranging from mild symptoms of heart failure late in life to the onset of sudden cardiac death at a young age and is caused by a mutation in one of the genes that encode a protein from the sarcomere, Z-disc or intracellular calcium modulators. Although many genes and mutations are already known to cause HCM, the molecular pathways that lead to the phenotype are still unclear. This review focus on the molecular mechanisms of HCM, the pathways from mutation to clinical phenotype and how the disease's genotype correlates with phenotype.

The authors present a rare case of hypertrophic cardiomyopathy associated with left ventricular noncompaction cardiomyopathy and coronary artery-left ventricular fistulae in a 42-year-old woman presenting with non-ST-elevation myocardial infarction. Coronary angiography, transthoracic echocardiography and cardiac magnetic resonance revealed the structural abnormalities of the left ventricle and the coronary tree., (Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.)

Background: Hypertrophic cardiomyopathy (HC) is the most frequent cardiac hereditary disease, caused by mutations in sarcomere protein coding genes. Although more than 430 mutations have been identified in several continents and countries, there have been no reports of mutations in Brazil., Objective: To carry out a genetic study to identify genetic mutations that cause HC in a group of patients in Espirito Santo, Brazil., Methods: Using the SSCP technique, 12 exons from the three main genes involved in HC were studied: exons 15, 20, 21, 22 and 23 of the beta-myosin heavy chain gene (MYH7), exons 7, 16, 18, 22 and 24 of the myosin binding protein C gene (MYBPC3) and exons 8 and 9 of troponin T gene (TNNT2)., Results: 16 alterations were found, including two mutations, one of them possibly pathogenic in the MYBPC3 gene (p. Glu441Lys) and another pathogenic one, previously described in the TNNT2 gene (p.Arg92Trp), 8 rare sequence variations and 6 sequence variations with allelic frequency higher than 1% (polymorphisms)., Conclusion: These data allow the conclusion that the genotyping of patients is feasible in our country. It is possible that the isolated p.Glu441Lys variant identified in exon 16 of the MYBPC3 gene is pathogenic, promoting a milder phenotype than that found when in association with other mutations. The p.Arg92Trp variant in the exon 9 of TNNT2 gene does not promote such a homogeneous phenotype as previously described and it can lead to severe hypertrophy.

Hypertrophic cardiomyopathy is a familial, genetic disease caused by mutations in genes encoding sarcomeric proteins. It is characterized by various deGrees of left ventricular hypertrophy, usually diffuse, predominantly involving the interventricular septum. The asymptomatic forms with mild or no segmental hypertrophy makes it difficult to establish the diagnosis and screening for familial forms. Its high penetrance is often incomplete and, as a result, 20% to 30% of adults who carry disease-causing gene mutations do not express the phenotype. The susceptibility to sudden death and likelihood of late expression makes establishing a preclinical diagnosis all the more important. The use of Doppler echocardiography and magnetic resonance imaging, in conjunction with a detailed ECG analysis, may be useful in this process. Molecular genetic studies can identify mutations in 60% to 80% of the cases. However, its complex, time-consuming and costly nature, coupled with an inadequate assessment of genotype-phenotype relationships, limits its routine application. Major advances in imaging methods and the introduction of more simplified molecular techniques may contribute to clinical and preclinical diagnosis of hypertrophic cardiomyopathy, in addition to allowing implementation of therapeutic strategies to prevent or delay the development of the disease.

Hypertrophic cardiomyopathy (HCM) is a primary disease of the sarcomere, with considerable genetic heterogeneity and variability in phenotypic expression, whose main complication is sudden cardiac death (SCD). Genetic aspects of HCM, its molecular pathophysiology and genotype-phenotype relationships are the subject of this review, which is aimed at better understanding of practical management in this patient population. As HCM is a genetic disease whose initial manifestation can be sudden death, it is essential to establish the diagnosis at an early stage, to proceed with risk stratification and implementation of SCD prevention strategies, and to promote genetic counseling of patients and screening of their families. Detection of pathological mutations through progressive sequencing of the genes most commonly involved is the most efficient way to diagnose HCM, even in the absence of clinical evidence of the disease. Identification of individuals at high risk of SCD is a major challenge in the management of this population, since SCD can be prevented by use of an implantable cardioverter-defibrillator. The selection of patients for prophylactic implantation of these devices, particularly those who have only one major risk factor, is currently the subject of controversy.

Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease and is often a consequence of mutations in the myosin-binding protein C gene (MYBPC3). Until now, however, no systematic review has been published on mutations of this gene in a Portuguese population., Objectives: In a Portuguese population of HCM patients: 1) to determine the prevalence of mutations in the MYBPC3 gene; 2) to characterize the mutations genetically; 3) to analyze the phenotype and compare it with the genotype-phenotype correlations for mutations in this gene described in the literature., Methods: We studied 45 consecutive index patients with HCM (41 with familial HCM). In each patient, we performed a genetic study to detect mutations in the MYBPC3 gene. Once a mutation was identified and genetically characterized, a broad phenotypic evaluation was performed. The genetic and clinical data were then compared with those described in the literature., Results: Of the 45 patients, 5 (11.1%) showed mutations in the MYBPC3 gene (2 deletions and 3 missense mutations), all in patients with familial HCM. Of these, 4 were 'new' mutations: Ala 522 Thr (exon 17); Gli 1205 Asp (exon 32); Lis 505 Del (exon 17) and Lis 813 Del (exon 25). The other mutation, Arg 502 Gln (exon 17), had been previously described in the literature. Three of the 5 mutations were located in exon 17. Four of these 5 patients were symptomatic, mainly with heart failure and supraventricular arrhythmias. No patient was at high risk for sudden cardiac death. Most of the patients had non-obstructive HCM. The ECG, echocardiogram, Holter monitoring and treadmill exercise test showed highly variable results, reflecting the heterogeneity typical of this disease., Conclusions: In a Portuguese population of 45 HCM patients, 5 (11.1%) had mutations in the MYBPC3 gene (3 missense mutations--theoretically less frequent in the MYBPC3 gene--and 2 deletions). Four of these were 'new' mutations and 3 of them were located in exon 17 (which may be a 'hot spot' for MYBPC3 gene mutations in the Portuguese population). In all the patients, the phenotypic expression was different from that usually described for these mutations; in 3 of our patients, the clinical manifestations and penetrance were of early onset and one patient had a highly symptomatic form of obstructive hypertrophic cardiomyopathy. These data reflect the large number of exceptions to the classic genotype-phenotype correlations in HCM, highlighting the role of other factors, genetic and non-genetic, in regulating penetrance, clinical expression and prognosis in each family and in each individual patient.

Hypertrophic cardiomyopathy (HCM) is a relatively common genetic disease, generally with a benign prognosis. However sudden cardiac death may occur, sometimes as the first manifestation of the disease. More than two hundred different mutations have been described in HCM, in 12 different genes encoding sarcomere proteins. This genetic diversity is accompanied by considerable clinical variability and it is likely that phenotype is partially determined by genotype. In recent years it has been suggested that genetic defects could be the major markers of prognosis. Thus, some mutations would carry a good prognosis whereas others, so-called 'malignant' mutations, would be associated with premature sudden death. In a Portuguese population of 35 index patients with HCM the authors found considerable genetic heterogeneity: seven of the 12 mutations identified were de novo, each family having its own 'private' mutation. Moreover, in two unrelated families with the same mutation (I263T--exon 9, missense) in the beta-myosin heavy chain gene (MYH7), penetrance, clinical expression and prognosis were quite different, particularly regarding the occurrence of sudden cardiac death. In two other also unrelated families, in each index patient a different mutation was identified in the troponin I gene (TNNI3): A157V (missense), exon 7 and S199N (missense), exon 8. Phenotypic expression was different but both patients suffered sudden cardiac death (one survived). This suggests that mutations in this gene carry an adverse prognosis. In conclusion, the considerable genetic and clinical variability found in HCM hinders the interpretation of genotype-phenotype correlations, particularly since all the published data is based on small numbers of families.

The gene encoding the beta-myosin heavy chain is one of the most frequently implicated in familial hypertrophic cardiomyopathy. Several mutations have been identified and some genotype-phenotype relationships have been assumed, particularly with regard to prognosis. Nevertheless, phenotypic expression is variable even in affected members of the same family carrying the same mutation. We identified the Ile263Thr mutation in several members of two unrelated Portuguese families. Penetrance, clinical behavior and prognosis were quite different between the two families, particularly concerning the occurrence of sudden death. Additional factors probably exist which account for the differences found. The complexity of hypertrophic cardiomyopathy makes it difficult to accurately determine genotype-phenotype relationships, and the screening and comparison of large affected families carrying the same mutation is warranted.

Objective: Cardiac evaluation (clinical, electrocardiographic and echocardiographic) of 25 Brazilian patients with clinical diagnosis of Friedreich's ataxia (FA) related to the frequency and the size of GAA repeats (unstable expansion of trinucleotide repeats that results in the disease)., Methods: Clinical and cardiac study including electrocardiogram and echocardiogram of all patients and molecular analysis to detect the frequency and the size of GAA expansion, by polymerase chain reaction analysis., Results: Homozygous GAA expansion was detected in 17 patients (68%) - all typical cases. In 8 (32%) cases (6 atypical and 2 typical), no GAA expansion was observed, therefore it was not considered Friedreich's ataxia. All patients with GAA expansion (100%) had electrocardiographic abnormalities, and only 25% of the cases without GAA expansion had some abnormality on this exam. However, only 6% of all patients revealed some signals/symptoms suggestive of cardiac involvement., Conclusion: A molecular analysis is essential to confirm the diagnosis of Friedreich's ataxia; however, an adequate cardiac evaluation, including an electrocardiogram, was extremely useful to better screening the patients which should perform these molecular analysis.

Introduction: The etiology of Familial Hypertrophic Cardiomyopathy (HCM) is attributed to the mutation of genes that encode sarcomeric proteins in the heart. Until now no gene mutations had been identified in Portuguese families with HCM., Objective: The main objective of this study is to describe a Portuguese family with HCM carrying an Arg403Gln mutation in the beta myosin heavy chain gene., Methods: With the help of several Molecular Biology tools, 40 families with HCM were studied. In all these families, one member was identified as carrying an Arg403Gln mutation in the beta myosin heavy chain gene. All family members were submitted to a physical exam, EKG and echocardiography. Those carrying a gene mutation were also submitted to Holter monitoring and to magnetic ressonance imaging., Results: Molecular biology techniques are extremely important for the diagnosis of HCM, particularly in healthy carriers., Conclusion: The use of molecular diagnostic tools in HCM is very useful because it allows us to identify the healthy carriers and establish earlier clinical and prevention programs for these individuals.

The introduction of molecular biology in Cardiology opened a new era, in which the collaboration between geneticists, molecular biologists and cardiologists will allow the clinical application of Molecular Cardiology. In this review the new advances in the diagnosis and prognostic evaluation of patients with Hypertrophic Cardiomyopathy at the molecular level are discussed. We also present a summary of our current knowledge on the genetic bases and molecular mechanisms of this disease. Finally, some possibilities of the future clinical application of the data obtained by Genetic and Molecular Biology are shown. The Molecular Biology of Hypertrophic Cardiomyopathy expanded our horizons beyond the morphologic definitions, exposing the limitations of traditional concepts. However, we should not forget the potential drawbacks of these genetic tests, in order to anticipate and prevent the problems associated with their performance.

The association of spontaneous complete heart block and hypertrophic cardiomyopathy is rare. We have studied three patients of the same family, two brothers and one nephew, ages 19-41 years, with hypertrophic cardiomyopathy confirmed by hemodynamic and angiographic studies. All patients were treated with permanent cardiac pacemaker implant. They are asymptomatic, aging 33 to 55 years, with follow-up of 157 to 176 months after the onset of the heart block.