Genetics in Hypertrophic Cardiomyopathy: An Evolving Clinical Landscape

Genomics in hypertrophic cardiomyopathy (HCM) are now 25 years old.1,2 The article of Li et al3 in this issue of the journal provides an opportunity to revisit and place into perspective several important principles related to the clinical application of genetic testing to the HCM patient population, thereby assessing progress in understanding this heterogeneous condition, the most common of the inherited heart diseases.4,5 Article see p 416 ### Genetic Testing Perhaps, most important is recognizing the current role achieved by genetic testing in contemporary HCM patient management and family screening. This technology has been available commercially in the United States since 2003, now with 4 fee-for-service companies that have brought advances in genomics for HCM and other genetic diseases out of the research laboratory, and widely available to clinicians.1,2 As a result, the landscape of HCM has changed in several ways. Notable in this regard is the emergence of a new patient subgroup known as gene positive-phenotype negative (ie, genetically affected family members without left ventricular hypertrophy).6 Recognition of relatives who are gene carriers and, therefore, at risk for developing clinical disease demonstrates the power of HCM mutational analysis not otherwise possible. However, the precise likelihood of incurring clinical disease, or the age at which phenotype conversion could occur, remain uncertain with the possibility that some patients will achieve advanced age without developing left ventricular hypertrophy. The most clinically impactful outcome of predictive family screening is the possibility of excluding those relatives without the family mutation from the risk of developing HCM and further clinical consideration.2 However, for such an initiative to be actionable, a pathogenic (disease-causing) mutation must be identified in a family member with clinically expressed HCM (ie, with left ventricular hypertrophy).2 Figure 1. Top , Distribution of genetic test …

Genetic counselling and genetic testing in hypertrophic cardiomyopathy (HCM) represent an integral part of the diagnostic algorithm to confirm the diagnosis, distinguish it from phenocopies, and suggest tailored therapeutic intervention strategies. Additionally, they enable cascade genetic testing in the family. With the implementation of Next Generation Sequencing technologies (NGS), the interpretation of genetic data has become more complex. In this regard, cardiologists play a central role, aiding geneticists to correctly evaluate the pathogenicity of the identified genetic alterations. In the ideal setting, geneticists and cardiologists must work side by side to diagnose HCM as well as convey the correct information to patients in response to their many questions and concerns. After a brief overview of the role of genetics in the diagnosis of HCM, we present and discuss the frequently asked questions by HCM patients throughout our 20-year genetic counselling experience. Appropriate communication between the team and the families is key to the goal of delivering the full potential of genetic testing to our patients.

More than two decades have elapsed since the discovery that sarcomere gene defects cause familial hypertrophic cardiomyopathy (HCM). Since then, genetic testing in HCM has developed and expanded, and is now widely available as a potential clinical service in the Western countries. In the meantime, however, the cross-talk between geneticists and clinicians has developed slowly, and still remains unstandardized, with modalities of interaction and degree of mutual comprehension that vary wildly in various settings. In addition, clinicians often question the clinical utility of genetic testing in HCM patients and their families. The apparent lack of practical benefit, in the face of considerable costs, has long hindered large-scale diffusion of genetic testing, particularly in developing countries, and still accounts for understandable (but not always justifiable) resistance on the part of the physicians. However, such resistance is in contrast with considerable evidence supporting a role for molecular diagnosis in tailoring management for HCM patients. We here review several sound clinical reasons in favour of systematic genetic testing in HCM, ranging from identification of complex genotypes, heralding severe disease expression and outcome, to the added benefit of multidisciplinary genetic teamwork, enhancing awareness towards inheritable diseases in the cardiology community. We hope to show that to underestimate the clinical potential of genetic testing in HCM, and to defer its implementation until more advanced knowledge becomes available, is to lose an important opportunity for present improvement in care.

Aims: A major breakthrough in the molecular genetics of hypertrophic cardiomyopathy (HCM) has made genetic testing now available in clinical practice, raising new questions about its implications, potential benefits, and...

More than two decades have elapsed since the discovery that sarcomere gene defects cause familial hypertrophic cardiomyopathy (HCM). Since then, genetic testing in HCM has developed, and become an important tool in clinical practice for diagnosis and prognosis overall in the Western countries. However its practical benefits are still understimated and clinicians often question about cost-effectiveness of genic testing in HCM patients and their families. This resistance is in contrast with considerable evidence supporting the role of genetics in tailoring management for HCM patients. Several current clinical uses of genetic testing in HCM, ranging from diagnosis in ambiguous situations, identification of disease phenocopies and HCM complex genotypes and confirmation of inherited disease in family members are reviewed. In the near future it is hoped that next generation sequencing will provide further diffusion of genetic testing in HCM and improvement in care.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiomyopathy usually caused by autosomal dominant variants in sarcomeric genes. This report summarises a 10-year retrospective study of HCM genetic testing in an ultraperipheral region. In our analysis we included all adult patients who underwent genetic testing for HCM between January 2015 and August 2025. Variants were classified according to the ACMG/AMP guidelines and the ClinGen Inherited Cardiomyopathy Expert Panel guidelines, with only likely pathogenic (LP) or pathogenic (P) findings considered as a positive test result. Patients with negative results, variants of uncertain significance, or phenocopies were excluded. Over this period, 140 patients with HCM underwent genetic testing, of whom 54 (39%) were found to carry a P or LP variant. Sixty-eight percent of cases were familial, representing a total of 15 families. Genetic analysis identified 9 distinct variants across 4 sarcomeric genes, 1 non-sarcomeric gene and 1 mitochondrial gene. Variants in MYH7 accounted for the majority of positive results. Most patients were single heterozygotes, with 2 exceptions: 1 patient was homozygous for a TNNT2 variant, and another harboured variants in both MYH7 and TNNT2. Regarding the MYH7, we identified 2 missense variants: the P c.1750G>C (p.Gly584Arg) detected in 39 patients from 11 families and the P/LP c.2389G>A (p.Ala797Thr), found in 4 patients from 2 families. Two LP variants in the MYBPC3 gene were detected: a missense variant, c.1484G>A (p.Arg495Gln), with 1 familial transmission; and 1 sporadic case, a multiexon deletion involving at least exons 26 to 32. A LP TNNI3 variant (c.586G>T, p.Asp196Tyr) was also identified in one patient. A consanguineous family with 4 affected members was found to carry the TNNT2 missense variant c.842A>T (p.Asn281Ile). One individual also carried the MYH7 variant c.1750G>C (p.Gly584Arg), representing a case of composite digenic heterozygosity. The coexistence of 2 variants was associated with earlier disease onset, greater atrial dilation but less hypertrophy compared to relatives carrying only one variant. Beyond the sarcomeric spectrum, we identified a rare truncating variant in the ALPK3 gene (c.3292G>T,p.Glu1098*;P) in a patient presenting with high-risk phenotypic features, including apical aneurysm, impaired systolic function and sustained ventricular arrhythmia. Additionally, we detected a homoplasmic LP mitochondrial variant in MT-TI (m.4300A>G) in a 40-year-old male with severe HCM and an implantable cardioverter-defibrillator (ICD). Given the maternal inheritance pattern and a family history of HCM in the mother and ICD implantation in a maternal uncle, this variant could provide a plausible explanation for the phenotype. In conclusion, genetic testing for HCM in our ultraperipheral region has revealed a diverse and unique spectrum of variants, illustrating the genetic heterogeneity and clinical complexity present in our geographically isolated population.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular diseases, with a prevalence of at least 1 in 500 in the general population.1,2 HCM is characterized by left ventricular hypertrophy, in the absence of other loading conditions, such as hypertension.3 The hallmark feature of HCM is significant clinical heterogeneity in presentation, ranging from asymptomatic patients to those who have the most serious outcomes of heart failure and sudden cardiac death. Over 1500 mutations in at least 15 sarcomere-encoding genes have been identified.4–7 The significance of cardiac genetic testing in clinical practice is 2-fold. For the proband, identification of the underlying genetic cause in some cases can clarify the cause of hypertrophy, for example, clarifying phenocopies, such as PRKAG2-glycogen storage disease and Fabry disease. The greatest utility, however, is in cascade genetic testing of asymptomatic relatives, with clear benefits either for confirming a borderline clinical diagnosis, or suspicious clinical changes suggestive of early disease, or most importantly ruling out the disease in those who test gene-negative. Identification of a silent gene carrier will guide cascade testing of additional family members, in effect clarifying their risk status. Of most benefit, a negative genetic result can reassure offspring that they are not at risk of HCM. The escalation in our understanding of the genetic basis of HCM has been catalyzed by the implementation of next generation sequencing technologies. In response to faster and more affordable testing, commercial genetic testing for HCM now often comprises vast cardiac gene chips (ie, 50–200 or more genes). This approach, although comprehensive, also draws into sharp focus the limitations of our current knowledge. The challenges of cardiac genetic testing are increasingly documented, such as identification of variants of uncertain significance (VUS), incidental genetic findings,8 reclassification of variants,9 increased need …

Building on seminal studies of the last 20 years, genetic testing for hypertrophic cardiomyopathy (HCM) has become a clinical reality in the form of targeted exonic sequencing of known disease-causing genes. This has been driven primarily by the decreasing cost of sequencing, but the high profile of genome-wide association studies, the launch of direct-to-consumer genetic testing, and new legislative protection have also played important roles. In the clinical management of hypertrophic cardiomyopathy, genetic testing is primarily used for family screening. An increasing role is recognized, however, in diagnostic settings: in the differential diagnosis of HCM; in the differentiation of HCM from hypertensive or athlete's heart; and more rarely in preimplantation genetic diagnosis. Aside from diagnostic clarification and family screening, use of the genetic test for guiding therapy remains controversial, with data currently too limited to derive a reliable mutation risk prediction from within the phenotypic noise of different modifying genomes. Meanwhile, the power of genetic testing derives from the confidence with which a mutation can be called present or absent in a given individual. This confidence contrasts with our more limited ability to judge the significance of mutations for which co-segregation has not been demonstrated. These variants of "unknown" significance represent the greatest challenge to the wider adoption of genetic testing in HCM. Looking forward, next-generation sequencing technologies promise to revolutionize the current approach as whole genome sequencing will soon be available for the cost of today's targeted panel. In summary, our future will be characterized not by lack of genetic information but by our ability to effectively parse it.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease with vast genetic heterogeneity, as demonstrated over the past two decades. Mutations in 11 or more genes encoding proteins of the cardiac sarcomere (> 1,400 variants) are responsible for (or associated with) HCM. Genetic testing has proved to be an invaluable tool in the evaluation and management of inherited cardiovascular diseases such as dilated cardiomyopathy, HCM, arrhythmogenic cardiomyopathies, and various channelopathies. HCM is an autosomal dominant disorder with DNA variants in the sarcomere genes which encode for sarcomeric proteins. The incorporation of genetic testing into the multi-disciplinary care of HCM patients helps to identify the molecular basis of the disease and thus improve diagnostic accuracy and refine management strategies. However, due to the inherent complexities of the human genome which transposes itself onto the process of genetic testing, it is crucial to understand the unique characteristics of such testing when applying it to routine clinical practice. These characteristics will play a major role in the interpretation of the genetic test results and underscore the realistic expectations of the clinician regarding the yield of the various types of genetic testing in HCM patients, which thus provides a foundation for applying personalized medicine and identifying specific phenotypic groups, including phenocopies, focused family screening, and a molecular medicine-based diagnosis. The genetic testing services in HCM must be provided by individuals with the necessary expertise in the interpretation of the test results; when not available, collaboration with specialized providers will be ideal.

[first paragraph of article]Hypertrophic cardiomyopathy (HCM) is defined as a primary cardiac muscle disease characterized by the presence of myocardial hypertrophy in the absence of apparent causes for the observed degree of hypertrophy. This definition includes both familial and sporadic (apparently non-familial) forms of the disease. HCM is usually considered as a genetically determined condition. Current genotyping technologies allow for the identification of the genetic causes of the disease in 50 to 70% of the patients who fulfill clinical diagnostic criteria. However, the etiology of 30 to 40% of the cases remains elusive. This review is focused on the current role of genetic testing in HCM, and the potential benefits of the identification of the genetic etiology of the disease.

IntroductionDiagnostic genetic testing is an integral part of patient management in hypertrophic cardiomyopathy (HCM). Over time, the number of genes included in diagnostic genetic panels increased. The aim of the...

Hypertrophic cardiomyopathy (HCM) is a common hereditary condition affecting approximately 1 in 500 adults. It is characterized by marked clinical heterogeneity with individuals experiencing minimal to no symptoms, while others may have more severe outcomes including heart failure and sudden cardiac death. Genetic testing for HCM is increasingly available due to advances in DNA sequencing technologies and reduced costs. While a diagnosis of HCM is a well‐supported indication for genetic testing and genetic counseling, incorporation of genetic services into the clinical setting is often limited outside of expert centers. As genetic counseling and testing have become more accessible and convenient, optimal integration of genomic data into the clinical care of individuals with HCM should be instituted, including delivery via genetic counseling. Drawing on recommendations from recent disease guidelines and systematic evidence reviews, we highlight key recommendations for HCM genetic testing and counseling. This practice resource provides a comprehensive framework to guide healthcare providers in the process of genetic test selection, variant classification, and cascade testing for genetic evaluation of HCM.

Background Hypertrophic cardiomyopathy (HCM) is a condition associated with an increased risk of sudden cardiac death (SCD). Post-mortem genetic testing of victims of SCD by HCM is crucial for early detection and risk stratification of family relatives. Case Presentation A 56-year-old male, with history of hypertension and dyslipidemia, was referred for cardiomyopathy screening, after his brother, a commercial airplane pilot, died suddenly at 51 years of age while driving a car. The brother had no known history of cardiac disease. As part of his cardiovascular assessment as a pilot, relatives reported that he had undergone an ECG several years ago (apparently normal), but he had never performed an echocardiogram. Surprisingly, autopsy findings revealed an enlarged heart with significant left ventricular hypertrophy (LVH) (wall thickness: 25mm), And post-mortem genetic testing identified a likely pathogenic MYH7 variant (c.2389G>A), establishing the cause of the SCD as a previously undiagnosed HCM. The patient’s initial transthoracic echocardiography in 2019 demonstrated mild concentric LVH and subsequent genetic screening revealed the same MYH7 variant in heterozygosity. In 2024, he experienced a dizziness episode upon postural transition. Echocardiography revealed a dynamic left ventricular outflow tract gradient of up to 70 mmHg in orthostasis, normal LA size and mild LVH. Beta-blocker was started and the patient became asymptomatic. Cardiac MRI revealed asymmetric septal hypertrophy (maximal thickness 15 mm in mid inferoseptal segment), mild intramural fibrosis in the basal inferolateral and mid inferior segments, and microvascular dysfunction. Holter monitoring had no significant abnormalities. HCM SCD risk score is estimated as <4%. The genetic testing was made available by the patient to his relatives, who live in other regions of the country, to ensure family screening. The patient remains asymptomatic under beta-blocker. Discussion This case underscores the importance of post-mortem genetic testing of victims of SCD by HCM, to initiate systematic family screening and identify at-risk individuals in the family. Additionally, the pilot’s SCD raises concerns regarding aviation safety and the adequacy of current cardiovascular screening protocols in commercial airplane pilots. The patient’s brother, a commercial pilot, succumbed to SCD while driving, an event that could have occurred during a flight. This case underlines the need to implement a rigorous, regular and systematic cardiovascular assessment protocol in aviation pilots. In professions, in which sudden incapacity poses significant safety risks, regular exams should be performed and echocardiography should be integrated into routine cardiovascular assessments to enhance screening strategies for heart disease.

Genetic testing in hypertrophic cardiomyopathy (HCM) is a valuable tool to manage patients and their families. Genetic testing can help inform diagnosis and differentiate HCM from other disorders that also...

BackgroundHCM is a disease characterised by otherwise unexplained hypertrophy of the myocardium, often as a result of a gene mutation. Phenotypic expression is estimated at 1 in 500 and genetic...