A bibliometric and visual analysis of research trends and hotspots of familial hypertrophic cardiomyopathy: A review.

Familial hypertrophic cardiomyopathy (FHCM) is an inherited cardiac disease caused by mutations of sarcomere proteins and can be the underlining substrate for major cardiovascular events. Early identification and diagnosis of FHCM are essential to reduce sudden cardiac death. So, this paper summarized the current knowledge on FHCM, and displayed the analysis via bibliometrics method. The relevant literature on FHCM were screened searched via the Web of Science Core Collection database from 2012 to 2022. The literatures were was summarized and analyzed via the bibliometrics method analyzed via CiteSpace and VOSviewer according to topic categories, distribution of spatiotemporal omics and authors, as well as references. Since 2012, there are 909 research articles and reviews related to FHCM. The number of publication for the past 10 years have shown that the development of FHCM research has been steady, with the largest amount of literature in 2012. The most published papers were from the United States, followed by the United Kingdom and Italy. The University of London (63 papers) was the institution that published the most research articles, followed by Harvard University (45 papers) and University College London (45 papers). Keywords formed 3 clusters, focused on the pathogenesis of FHCM, the diagnosis of FHCM, FHCM complications, respectively. The bibliometric analysis and visualization techniques employed herein highlight key trends and focal points in the field, predominantly centered around FHCM's pathogenesis, diagnostic approaches, and its complications. These insights are instrumental in steering future research directions in this area.

A New Leu714Arg Variant in the Converter Domain of MYH7 is Associated with a Severe Form of Familial Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy is the most frequent autosomal dominant disease, yet due to genetic heterogeneity, incomplete penetrance, and phenotype variability, the prognosis of the disease course in pathogenic variant carriers remains an issue. Identifying common patterns among the effects of different genetic variants is important. METHODS: We investigated the cause of familial hypertrophic cardiomyopathy (HCM) in a family with two patients suffering from a particularly severe disease. Searching for the genetic variants in HCM genes was performed using different sequencing methods. RESULTS: A new missense variant, p.Leu714Arg, was identified in exon 19 of the beta-myosin heavy chain gene (MYH7). The mutation was found in a region that encodes the 'converter domain' in the globular myosin head. This domain is essential for the conformational change of myosin during ATP cleavage and contraction cycle. Most reports on different mutations in this region describe severe phenotypic consequences. The two patients with the p.Leu714Arg mutation had heart failure early in life and died from HCM complications. CONCLUSIONS: This case presents a new likely pathogenic variant in MYH7 and supports the hypothesis that myosin converter mutations constitute a subclass of HCM mutations with a poor prognosis for the patient.

Generation of induced pluripotent stem cell lines from two unrelated individuals with familial hypertrophic cardiomyopathy carrying MYBPC3 nonsense mutations.

Familial hypertrophic cardiomyopathy (HCM) stands as a predominant heart condition, characterised by left ventricle hypertrophy in the absence of any associated loading conditions, with affected individuals having an increased risk of developing heart failure and sudden cardiac death (SCD). Two induced pluripotent stem cell (iPSC) lines were derived from peripheral blood mononuclear cells obtained from two unrelated individuals with previously reported nonsense mutations in the MYBPC3 gene. The first individual is a 48-year-old male (F26) with the MYBPC3 c.1731G > A HCM mutation, whereas the second individual is a 43-year-old female (F82) carrying the MYBPC3 c.2670G > A HCM mutation. The generated iPSCs exhibit appropriate expression of pluripotency markers, trilineage differentiation capacity and a normal karyotype. This resource contributes to gaining deeper insights into the pathophysiological mechanisms that underlie HCM.

Generation of induced pluripotent stem cell lines from two unrelated individuals with familial hypertrophic cardiomyopathy carrying the MYBPC3 missense c.1484G>A mutation.

Familial hypertrophic cardiomyopathy (HCM) is the most common inherited heart condition. HCM patients show left ventricle hypertrophy without any associated loading conditions, being at risk for heart failure and sudden cardiac death. Two induced pluripotent stem cell (iPSC) lines were generated from peripheral blood mononuclear cells obtained from two unrelated individuals, a 54-year-old male (F81) and a 44-year-old female (F93), both carrying the MYBPC3 c.1484G>A HCM mutation. iPSCs show expression of pluripotency markers, trilineage differentiation capacity and a normal karyotype. This resource enables further assessment of the pathophysiological development of HCM.

Familial Hypertrophic Cardiomyopathy: Diagnosis and Management.

Hypertrophic cardiomyopathy (HCM) is widely recognized as one of the most common inheritable cardiac disorders. Since its initial description over 60 years ago, advances in multimodality imaging and translational genetics have revolutionized our understanding of the disorder. The diagnosis and management of patients with HCM are optimized with a multidisciplinary approach. This, along with increased safety and efficacy of medical, percutaneous, and surgical therapies for HCM, has afforded more personalized care and improved outcomes for this patient population. In this review, we will discuss our modern understanding of the molecular pathophysiology that underlies HCM. We will describe the range of clinical presentations and discuss the role of genetic testing in diagnosis. Finally, we will summarize management strategies for the hemodynamic subtypes of HCM with specific emphasis on the rationale and evidence for the use of implantable cardioverter defibrillators, septal reduction therapy, and cardiac myosin inhibitors.

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model.

Familial hypertrophic cardiomyopathy (HCM, OMIM: 613690) is the most common cardiomyopathy in China. However, the underlying genetic etiology of HCM remains elusive. We previously identified a myosin heavy chain 7 (MYH7) gene heterozygous variant, NM_000257.4: c.G2468A (p.G823E), in a large Chinese Han family with HCM. In this family, variant G823E cosegregates with an autosomal dominant disorder. This variant is located in the lever arm domain of the neck region of the MYH7 protein and is highly conserved among homologous myosins and species. To verify the pathogenicity of the G823E variant, we produced a C57BL/6N mouse model with a point mutation (G823E) at the mouse MYH7 locus with CRISPR/Cas9-mediated genome engineering. We designed gRNA targeting vectors and donor oligonucleotides (with targeting sequences flanked by 134 bp of homology). The p.G823E (GGG to GAG) site in the donor oligonucleotide was introduced into exon 23 of MYH7 by homology-directed repair. A silenced p.R819 (AGG to CGA) was also inserted to prevent gRNA binding and re-cleavage of the sequence after homology-directed repair. Echocardiography revealed left ventricular posterior wall (LVPW) hypertrophy with systole in MYH7 G823E/- mice at 2 months of age. These results were likewise validated by histological analysis (Figure 3). These results demonstrate that the G823E variant plays an important role in the pathogenesis of HCM. Our findings enrich the spectrum of MYH7 variants linked to familial HCM and may provide guidance for genetic counseling and prenatal diagnosis in this Chinese family.

MicroRNA expression profiles in familial hypertrophic cardiomyopathy with myosin-binding protein C3 (MYBPC3) gene mutations.

Familial hypertrophic cardiomyopathy (FHCM) is an autosomal dominant inherited disease caused by mutations in genes encoding cardiac sarcomere proteins. MicroRNAs (miRNAs) play an important role in the pathogenesis of FHCM. In the present study, we aimed to determine the miRNA profile in FHCM patients with myosin-binding protein C3 (MYBPC3) gene mutations. We recruited three FHCM patients and age- and sex-matched controls. The three probands all had hypertrophic obstructive cardiomyopathy with severe myocardial hypertrophy, and two of the three had a history of sudden cardiac death, representing a "malignant" phenotype. We then compared the miRNA expression profiles of three FHCM patients carrying MYBPC3 gene mutations with those of the normal control group using miRNA sequencing technology. Differentially expressed miRNAs were verified using real-time polymerase chain reaction (qPCR). Target genes and signaling pathways of the identified differentially expressed miRNAs were predicted using bioinformatics analysis. A total of 33 significantly differentially expressed miRNAs were detected in the peripheral blood of the three probands, of which 28 were upregulated, including miR-208b-3p, and 5 were downregulated. Real-time PCR confirmed the upregulated expression of miR-208b-3p in FHCM patients (P < 0.05). Bioinformatics analysis showed that miR-208b-3p was mainly enriched in 79 target genes including UBE2V2, MED13, YBX1, CNKSR2, GATA4, andSOX5/6, et al. Gene ontology (GO) analysis of target genes showed that miR-208b was mainly involved in the processes of negative regulation of transcription from RNA polymerase II promoter, and regulation of transcription, DNA templated. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the target genes regulated by miR-208b-3p were mainly involved in the Wnt signaling pathway. These findings suggest that FHCM patients with MYBPC3 gene mutations have a specific miRNA expression profile, and that miR-208b-3p is significantly upregulated in cardiac hypertrophy. Our results also indicate that miRNA-208b-3p activates the Wnt signaling pathway through its target gene to promote cardiac hypertrophy.

Effect of Cis-Compound Variants in MYH7 on Hypertrophic Cardiomyopathy With a Mild Phenotype.

Patients with hypertrophic cardiomyopathy (HC) caused by compound variants have severe clinical manifestations, but significant clinical heterogeneity remains. Clinical diversity in these patients may result from different combinations of variants. We analyzed the role of cis-compound variants in a Chinese HC pedigree. Exome sequencing was performed in the proband. Identified variants were detected with bi-directional Sanger sequencing in a pedigree that comprised 3 generations and 28 family members. Follow-up was performed for 16 years. Two missense variants (c.2465T>C, p.Met822Thr; c.4258C>T, p.Arg1420Trp) were identified in the MYH7 gene. These variants were absent in our 761 in-house people without HC and predicted to be pathogenic.Both variants were detected in 11 family members, thus they were believed to inherit cis. In the 11 members, only 5 developed HC, the other 6 were asymptomatic variant carriers with an abnormal electrocardiogram. The HC members had mild hypertrophy with a maximum left ventricular wall thickness of 13 to 21 mm and showed a low incidence of cardiovascular events. In conclusion, the cis-compound variants of Met822Thr and Arg1420Trp in MYH7 are causal but relatively benign, variants associated with familial HC. This finding suggests that different types of compound variants might need to be analyzed for a genotype-phenotype study.

Myocardial Perfusion Defects in Hypertrophic Cardiomyopathy Mutation Carriers.

Background Impaired myocardial blood flow (MBF) in the absence of epicardial coronary disease is a feature of hypertrophic cardiomyopathy (HCM). Although most evident in hypertrophied or scarred segments, reduced MBF can occur in apparently normal segments. We hypothesized that impaired MBF and myocardial perfusion reserve, quantified using perfusion mapping cardiac magnetic resonance, might occur in the absence of overt left ventricular hypertrophy (LVH) and late gadolinium enhancement, in mutation carriers without LVH criteria for HCM (genotype-positive, left ventricular hypertrophy-negative). Methods and Results A single center, case-control study investigated MBF and myocardial perfusion reserve (the ratio of MBF at stress:rest), along with other pre-phenotypic features of HCM. Individuals with genotype-positive, left ventricular hypertrophy-negative (n=50) with likely pathogenic/pathogenic variants and no evidence of LVH, and matched controls (n=28) underwent cardiac magnetic resonance. Cardiac magnetic resonance identified LVH-fulfilling criteria for HCM in 5 patients who were excluded. Individuals with genotype-positive, left ventricular hypertrophy-negative had longer indexed anterior mitral valve leaflet length (12.52±2.1 versus 11.55±1.6 mm/m2, P=0.03), lower left ventricular end-systolic volume (21.0±6.9 versus 26.7±6.2 mm/m2, P≤0.005) and higher left ventricular ejection fraction (71.9±5.5 versus 65.8±4.4%, P≤0.005). Maximum wall thickness was not significantly different (9.03±1.95 versus 8.37±1.2 mm, P=0.075), and no subject had significant late gadolinium enhancement (minor right ventricle‒insertion point late gadolinium enhancement only). Perfusion mapping demonstrated visual perfusion defects in 9 (20%) carriers versus 0 controls (P=0.011). These were almost all septal or near right ventricle insertion points. Globally, myocardial perfusion reserve was lower in carriers (2.77±0.83 versus 3.24±0.63, P=0.009), with a subendocardial:subepicardial myocardial perfusion reserve gradient (2.55±0.75 versus 3.2±0.65, P=<0.005; 3.01±0.96 versus 3.47±0.75, P=0.026) but equivalent MBF (2.75±0.82 versus 2.65±0.69 mL/g per min, P=0.826). Conclusions Regional and global impaired myocardial perfusion can occur in HCM mutation carriers, in the absence of significant hypertrophy or scarring.

Identification of three novel pathogenic mutations in sarcomere genes associated with familial hypertrophic cardiomyopathy based on multi-omics study.

BACKGROUND: Familial hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death, but exhibits heterogeneous clinical features. A major research focus is to identify specific ultrasonic phenotypes, and causal gene mutations, as well as to elucidate the possible metabolic pathogenic effects in familial HCM through multi-omics study. METHODS: Nine members of two familial HCM pedigrees were enrolled in this study. Their clinical data were collected, and the data of multiparameter ultrasound, whole-exome sequencing, and untargeted metabolomics were analyzed. RESULTS: We identified three novel pathogenic sarcomere gene mutations, TNNT2-rs397516484, MYH6-rs372446459 and MYBPC3-rs786204339 in two familial HCM pedigrees. The proband of Family 1 and his father carried TNNT2-rs397516484 and MYH6-rs372446459 missense mutations, while the proband of Family 2 and her brother carried MYBPC3-rs786204339 frameshift mutation. They presented with heart failure and abnormal electrocardiogram, accompanied by diastolic and systolic dysfunction and impaired myocardial work. They also showed disturbances of carbohydrate metabolism, including the citrate cycle (TCA cycle), glycolysis/gluconeogenesis, fructose and mannose metabolism, pentose and glucuronate interconversions and amino sugar and nucleotide sugar metabolism. CONCLUSIONS: Novel TNNT2-rs397516484, MYH6-rs372446459, and MYBPC3-rs786204339 are pathogenic sarcomere gene mutations in familial HCM, leading to decreased cardiac function and metabolic disturbances of carbohydrate metabolism, which have important implications for biologically defined diagnoses and precision medicine.

Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach.

Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways.

Hypertrophic Cardiomyopathy in Pregnancy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac condition and highly heterogeneous. Echocardiography and genetic and clinical screening have led to detection in women of childbearing age. Maternal and fetal outcomes among women with HCM are favorable. Genetic counseling is recommended. Prepregnancy clinical evaluation and risk assessment are paramount in ensuring optimal outcomes. Most women carry moderate risk of morbidity, have clinical evaluations and echocardiography each trimester, and deliver vaginally. Those who are symptomatic or have significant left ventricular outflow obstruction or recurrent arrhythmias prior to pregnancy are at higher risk and should be monitored at least monthly.

Hereditary Hypertrophic Cardiomyopathy in Children and Young Adults-The Value of Reevaluating and Expanding Gene Panel Analyses.

INTRODUCTION: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested "gene-negative" for familial predominantly pediatric CM, in hopes of finding a causative gene variant. METHODS: 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with "gene-negative" results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant gene, the index patient and both parents underwent clinical (i.e., partial) exome sequencing (trio-exome) in order to catch pathogenic variants linked to the disease in genes that were not included in the CM panel. RESULTS: The mean age at clinical presentation of the 10 index cases was 12.5 years (boys 13.4 years, n = 8; girls 9 years, n = 2) and the family history burden was 33 HCM/CM cases including 9 HCM-related SCD and one heart transplantation. In 5 (50%) families we identified a genetic variant classified as pathogenic or likely pathogenic, in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria, in MYH7 (n = 2), RBM20, ALPK3, and PGM1, respectively, and genetic variants of unknown significance (VUS) segregating with the disease in an additional 3 (30%) families, in MYBPC3, ABCC9, and FLNC, respectively. CONCLUSION: Our results show the importance of renewed thorough clinical assessment and the necessity to challenge previous genetic test results with more comprehensive updated gene panels or exome sequencing if the initial test failed to identify a causative gene for early onset CM or SCD in children. In pediatric cardiomyopathy cases when the gene panel still fails to detect a causative variant, a trio exome sequencing strategy might resolve some unexplained cases, especially if a multisystemic condition is clinically missed.

Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. HCM is a recognized genetic disorder most often caused by mutations involving myosin-binding protein C (MYBPC3) and ß-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identified mutations. METHODS: As a part of the international multidisciplinary SILICOFCM project ( www.silicofcm.eu ) the present study evaluated the association between underlying genetic mutations and clinical phenotype in patients with HCM. Only patients with confirmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study and divided into two groups accordingly. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Each patient underwent clinical examination and echocardiography. RESULTS: The most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). The MYBPC3 group had a significantly higher number of patients with a positive family history of HCM (46% vs. 7%; p = 0.014). There was a numerically higher prevalence of atrial fibrillation in the MYH7 group (60% vs. 35%, p = 0.085). Laboratory analyses revealed normal levels of creatinine (85.5 ± 18.3 vs. 81.3 ± 16.4 µmol/l; p = 0.487) and blood urea nitrogen (10.2 ± 15.6 vs. 6.9 ± 3.9 mmol/l; p = 0.472) which were similar in both groups. The systolic anterior motion presence was significantly more frequent in patients carrying MYH7 mutation (33% vs. 10%; p = 0.025), as well as mitral leaflet abnormalities (40% vs. 19%; p = 0.039). Calcifications of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p = 0.001). The difference in diastolic function, i.e. E/e' ratio between the two groups was also noted (MYBPC3 8.8 ± 3.3, MYH7 13.9 ± 6.9, p = 0.079). CONCLUSIONS: Major findings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.

Gap junction protein beta 4 plays an important role in cardiac function in humans, rodents, and zebrafish.

AIMS: GJB4 encodes a transmembrane connexin protein (Cx30.3) that is a component of gap junctions. This study investigated whether GJB4 plays an important role in human heart disease and function. METHODS AND RESULTS: We examined a patient and her older brother who both presented with complicated severe hypertrophic cardiomyopathy (HCM) and whose parents are healthy married cousins. The gene exome analysis showed 340 single nucleotide polymorphisms (SNPs) that caused amino acid changes for which the patient was homozygous and both parents were heterozygous. After excluding all known common (>10%) SNP gene mutations, the gene for GJB4 was the only identified gene that is possibly associated with cardiac muscle. The resultant E204A substitution exists in the 4th transmembrane domain. GJB4-E204A impaired the binding with gap junction protein A1 (GJA1) compared with GJB4-WT. The expression of GJB4 was induced in rat disease models of left and right ventricle hypertrophy and mouse disease models of adriamycin-induced cardiomyopathy and myocardial infarction, while it was not detected at all in control. An immunohistochemical study was performed for autopsied human hearts and the explanted heart of the patient. GJB4 was expressed and colocalized with GJA1 in intercalated discs in human diseased hearts, which was extensively enhanced in the explanted heart of the patient. The abnormal expression and localization of GJB4 were observed in beating spheres of patient's induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). We generated knockout zebrafish of GJB4 by CRISPR/Cas9 and the endodiastolic volume and the ventricular ejection fraction were significantly lower in GJB4-deficient than in wild-type zebrafish at five days post-fertilization. CONCLUSIONS: These results indicate both that GJB4 is defined as a new connexin in diseased hearts, of which mutation can cause a familial form of HCM, and that GJB4 may be a new target for the treatment of cardiac hypertrophy and dysfunction.

A novel nonsense mutation in TNNT2 in a Chinese pedigree with hypertrophic cardiomyopathy: A case report.

RATIONALE: Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease and a common cause of sudden cardiac death, heart failure, atrial fibrillation and stroke. In families affected by HCM, genotyping is useful for identifying susceptible relatives. In the present study, we investigated the disease-causing mutations in a three-generation Chinese family with HCM using whole exome sequencing (WES). PATIENT CONCERNS: The proband, a 50-year-old man, was diagnosed with HCM at the age of 41 years. He presented with an asymmetric hypertrophic interventricular septum and a maximum interventricular septum thickness of 18.04 mm. His third elder sister, niece and daughter were also clinically affected by HCM. DIAGNOSIS: Autosomal dominant HCM. INTERVENTIONS: Seven family members, including 4 affected members, accepted WES. The genetic variants were subsequently called using Genome Analysis Toolkit and annotated using the InterVar program. Following frequency filtration by the Genome Aggregation Database, the variants were evaluated using an in-house bioinformatics analysis pipeline. OUTCOMES: HCM was transmitted as an autosomal dominant trait in the family. An extremely rare stop gained mutation, rs796925245 (g.1:201359630G>A, c.835C>T, p.Gln279Ter) in the troponin T2 (TNNT2) gene was identified as the disease-causing mutation. The stop gained mutation was predicted to result in a truncated troponin T protein in cardiac sarcomere. An adolescent family member who had normal echocardiographic measurements was found to carry the same disease-causing mutation. LESSONS: A novel nonsense TNNT2 mutation was identified as the HCM-causing mutation in this Chinese pedigree. Since HCM shows a low penetrance by clinical criteria in adolescents, the adolescent mutation carrier, who is still clinically unaffected, should be offered routine follow-ups and sport activity recommendations to prevent adverse events including sudden cardiac death in the future.

Hypertrophic Cardiomyopathy　- A Heterogeneous and Lifelong Disease in the Real World.

Hypertrophic cardiomyopathy (HCM) is the most frequent hereditary cardiomyopathy, showing an autosomal-dominant f inheritance. A great deal of attention has been paid to genetics, left ventricular tract obstruction and the prediction and prevention of sudden cardiac death in HCM. Needless to say, these are very important, but we should recognize the heterogeneity in etiology, morphology, clinical course and management of this unique cardiomyopathy. Another important perspective is that HCM causes left ventricular remodeling over time and is a disease that requires lifelong management in the real world.

Familial evaluation reveals a distinct genetic cause in a large Spanish family with neurofibromatosis 1 and hypertrophic cardiomyopathy.

Neurofibromatosis 1 (NF1) is an autosomal dominant disorder characterized by café-au-lait spots, intertriginous freckling, and multiple neurofibromas. Classically, it has been described that hypertrophic cardiomyopathy (HCM) may be a cardiovascular manifestation of neurofibromatosis 1, although the relationship between these two entities has not been fully established. We report a large Spanish family carrying a pathogenic truncating variant in NF1 (p.Arg2258Ter) causing neurofibromatosis 1, and a pathogenic missense variant in MYH7 (p. Arg453Cys), causing hypertrophic cardiomyopathy independently. A complete penetrance was observed in both genetic diseases, reinforcing the notion of deleterious effects of both rare variants. According to our report, hypertrophic cardiomyopathy in patients with NF1 should not be considered as part of the clinical spectrum in all cases. A careful and comprehensive assessment, including family evaluation and genetic testing for HCM should be considered as part of the diagnostic work-up in individuals presenting with both phenotypes.