Review Article

Genetics in Hypertrophic Cardiomyopathy: An Evolving Clinical Landscape

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Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is characterised by unexplained increased wall thickness. Traditionally considered a monogenic disorder, emerging evidence highlights its complex genetic architecture. Genetic testing is now a cornerstone for diagnosis and family screening, although its prognostic and therapeutic impact at the individual level remains limited at present but is expected to grow as more comprehensive approaches are developed. Aimed at general cardiologists, this review summarises the benefits and limitations of current knowledge and genetic testing in HCM, and offers practical guidance on patient selection, interpretation of results, and integration into routine care. In this context, the challenge posed by variants of uncertain significance is discussed, and current and emerging strategies for their re-interpretation are outlined in brief. An updated overview is also provided of the genetic landscape, covering sarcomeric and non-sarcomeric genes, HCM phenocopies and new inheritance models, including oligogenic and polygenic mechanisms. Additionally, the potential of expanded genetic panels incorporating novel candidate genes and deep intronic and structural variants is highlighted. As gene therapy emerges as a future therapeutic option, precise molecular diagnosis will be essential for integrating genetic insights into routine clinical practice and advancing personalised care in HCM.

Keywords

Hypertrophic cardiomyopathy, genetic testing, inherited cardiomyopathy, precision medicine, sarcomeric genes, genotype–phenotype correlation,

Received:

Accepted:

Published online:

DOI: https://doi.org/10.15420/cfr.2025.12

Disclosure: The authors have no conflicts of interest to declare.

Correspondence: Juan Pablo Ochoa, Grupo de Miocardiopatías Hereditarias, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernandez Almagro, 3, 28029 Madrid, Spain. E: jpochoaf@cnic.es

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

For many cardiologists, cardiovascular genetics is still perceived as primarily a research endeavour or an academic exercise. While it is true that genetic testing and the management of inherited cardiovascular diseases often require specialised expertise and are best handled in dedicated inherited cardiac disease units, the increasing availability of genetic testing and the imminent development of targeted therapies for cardiomyopathies are set to make cardiovascular genetics an integral part of everyday clinical practice.

This review is aimed at cardiologists seeking to deepen their understanding of the genetic basis of hypertrophic cardiomyopathy (HCM), one of the most common genetic cardiovascular disorders. Traditionally estimated to affect 1 in 500 adults, recent epidemiological studies suggest that the actual prevalence may be significantly higher, potentially reaching 1 in 250–350.1 Although the disease course is variable, many patients experience adverse clinical outcomes, including heart failure (HF), arrhythmias and sudden cardiac death (SCD).

HCM is currently defined as a primary hereditary disease of the cardiac muscle, characterised by thickening of the left ventricular (LV) wall (≥15 mm) not explained by abnormal loading conditions, such as hypertension or valvular disease. However, our understanding of HCM has evolved significantly over time.

On the one hand, HCM is not necessarily synonymous with a specific molecular aetiology. Rather than being a definitive diagnosis, it is more accurately described as a phenotypic expression of various underlying conditions. This perspective is reinforced by the 2023 cardiomyopathy guidelines, which emphasise that, although the initial diagnosis is based on clinical features, an aetiological diagnosis must follow in which genetic testing plays a crucial role.2

On the other hand, since the first genetically proven cases of HCM were described in the 1990s, advances in next-generation sequencing (NGS) and bioinformatics have reshaped our understanding of the genetic architecture of the disease.3 The traditional monogenic, Mendelian model, in which a single, high-impact variant determines disease susceptibility, is now complemented by a more complex paradigm incorporating oligogenic and polygenic inheritance. Emerging evidence suggests that these alternative inheritance patterns may account for a subset of cases and, crucially, influence phenotype expression in individuals carrying likely pathogenic (LP) or pathogenic (P) variants (LP/P variants) in known HCM-related genes.4

This review aims to:

  • Examine the role of genetic background in increased wall thickness/HCM and evaluate how genetic testing (along with its current benefits and limitations) shapes patient care.
  • Provide practical guidance on identifying patients suitable for genetic testing, while outlining key considerations both when requesting the test and when interpreting the results.
  • Offer an updated overview of the genetic architecture of HCM, including classic sarcomeric genes, minor genes, HCM phenocopies, and emerging inheritance models such as oligogenic and polygenic mechanisms.

While this review primarily focuses on monogenic disorders, given that clinical testing for them is currently available, we also provide an overview of oligogenic and polygenic inheritance, recognising that diagnostic testing for polygenic causes is likely to become clinically accessible in the future.

With the growing role of genetics in cardiology, understanding these concepts will become increasingly relevant not only for specialists, but also for every cardiologist involved in patient care.

Why Perform Genetic Testing? The Role of Genetics in the Management of HCM Patients

Genetic testing has become an integral part of the clinical evaluation of HCM, with current guidelines recommending its use for all patients with a class 1 recommendation.2,5 Establishing a molecular diagnosis offers several clinical advantages for patients and families, but there are also limitations to acknowledge:

Benefits of Genetic Testing

Accurate Aetiological Diagnosis and Improved Patient Management

HCM represents a final common phenotype that can arise from multiple genetic aetiologies. Identifying a causative variant is critical for confirming the aetiological diagnosis of HCM. As we will see, understanding the aetiology enables us to define the natural history and clinical course, and to practice more personalised medicine. It might also be helpful in borderline cases, when increased wall thickness may be attributable either to early sarcomeric HCM or to secondary causes such as hypertension.

Genetic testing is also essential to distinguish true sarcomeric disease from phenocopies, including lysosomal and glycogen storage disorders (e.g. Danon, Fabry, Pompe’s disease), RASopathies (e.g. Noonan, Costello, cardiofaciocutaneous syndromes) and infiltrative conditions such as amyloidosis. Although relatively uncommon, phenocopies are identified in approximately 1–1.5% of adult patients with a clinical diagnosis of HCM, as reported both in our recently published cohort and in previous studies.6,7 Their recognition is critical, given that prognosis and management differ substantially and, in some cases, disease-specific therapies are available. See the Hypertrophic Phenotypes Secondary to Phenocopies section for more details.

Family Management (Cascade Genetic Screening)

One of the most significant advantages of genetic testing, particularly in a clinical setting, is its impact on family management. Once an LP/P variant is identified in a family, predictive genetic testing should be offered to asymptomatic relatives for early identification, risk-based surveillance and timely intervention. In relatives with subtle or inconclusive clinical findings, genetic testing of the identified variant can also aid in confirming the diagnosis and informing clinical decisions. More details on cascade screening are in the Who Should Be Tested? section.

Genetic Counselling

Genetic testing is an integral component of genetic counselling for inherited cardiac conditions, given that it provides essential information that enhances the accuracy of risk assessment and enables personalised clinical guidance. Test results can clarify inheritance patterns, inform reproductive planning and offer patients and their families a clearer understanding of the genetic basis of the disease. This knowledge supports informed decision-making and may also help reduce uncertainty, anxiety and feelings of guilt.8 Ultimately, incorporating genetic testing into the counselling process can improve patient engagement, strengthen family communication and support long-term disease management.8

Prognostic Information (Emerging Role)

HCM exhibits substantial clinical and genetic heterogeneity, making risk stratification challenging. Registry-based studies suggest that patients with pathogenic variants in sarcomere genes have a higher risk of adverse outcomes, including arrhythmias, SCD, HF and cardiovascular mortality, compared with those without identifiable sarcomere gene variants.9–12

Furthermore, some gene- and domain-specific correlations have been described. For example, truncating MYBPC3 variants (the most common pathogenic variants in HCM) tend to have a relatively homogeneous prognosis.13 In contrast, missense pathogenic variants in MYH7 show variable clinical expression depending on their localisation and can sometimes have prognostic implications.14 Notably, variants located in the converter domain or ATP-binding regions are associated with worse outcomes.15 Similar genotype–phenotype correlations have been described for TNNT2 (cardiac troponin T) and TNNI3 (cardiac troponin I) pathogenic variants.16,17

However, these observations have not yet translated into major changes in individual patient management. The HCM Risk-SCD calculator does not currently incorporate genetic information, and current guidelines do not recommend using sarcomeric pathogenic variant status to guide ICD implantation for primary prevention in individuals with low or intermediate SCD risk scores.2 This is because the independent predictive value of sarcomeric pathogenic variants for SCD risk remains unproven. However, this stance is likely to reflect a lack of sufficient evidence rather than inconsistencies in findings. Given this uncertainty, ICD implantation decisions for patients with sarcomeric pathogenic variants and intermediate risk scores will most likely require shared decision-making between the treating physician and the patient, taking into account the overall clinical context, patient preferences and emerging genotype-specific risk data. As research advances, genetic information is expected to refine risk prediction models by integrating insights into the natural history associated with specific genes, functional regions and individual variants, and potentially also through the incorporation of polygenic risk scores.

Cost-effectiveness

Genetic screening is more cost-effective than clinical screening alone.18 In cases of HCM with autosomal dominant inheritance, which represents the majority of cases, each first-degree relative has a 50% chance of inheriting the familial variant. When an LP/P variant is identified, predictive cascade testing enables healthcare resources to focus on genotype-positive relatives, while safely discharging genotype-negative individuals from lifelong monitoring. This strategy not only optimises healthcare efficiency and reduces unnecessary anxiety, it also generates a multiplier effect, given that a single genetic diagnosis can translate into downstream benefits for multiple family members through targeted surveillance and tailored management.8

Current Limitations of Genetic Testing

Despite the mentioned benefits, some challenges limit the current impact of genetic testing in HCM such as:

Incomplete Diagnostic Yield

The diagnostic yield of genetic testing in HCM ranges from 25% to 50%, depending on factors such as disease severity, age of onset, familial aggregation and clinical features.19 Importantly, a negative result does not exclude diagnosis. In such cases, cardiologists should carefully assess the scope of the test performed, highlighting the need for thoughtful interpretation (see sections How to Test and Gene-elusive Hypertrophic Cardiomyopathy for more information). Nonetheless, even with a comprehensive NGS study, a significant subset of cases remains genetically unresolved.6

Inconclusive Results: Variants of Uncertain Significance

Variants of uncertain significance (VUS) represent one of the main limitations of genetic testing in HCM, as in other inherited diseases. Their frequency has increased with the wider use of large multigene panels, the extension of testing to patients with borderline phenotypes, and the incorporation of novel genes.20,21

Underrepresentation of many populations in reference databases (e.g. Asian, Black, Hispanic, Pacific Islander, Ashkenazi and Sephardic Jewish) further contributes to VUS reporting, given that variants common in these groups may be incorrectly labelled as rare.22,23

VUS results pose significant clinical challenges. They generate uncertainty for both patients and providers, complicating counselling, family management and clinical decision-making. They are also associated with increased patient anxiety, misinterpretation of results, reduced uptake of family screening and lower rates of information sharing with relatives.24,25

Although the American College of Medical Genetics and Genomics (ACMG) has developed standardised guidelines for variant classification, their application in cardiology remains complex.26 Accurate interpretation requires the integration of evidence from laboratory reports, curated variant databases, literature, segregation studies, and often expert consultation. Laboratory expertise in this context is crucial to ensure a thorough evaluation that incorporates the latest scientific evidence and ensures that genetic findings are appropriately integrated into clinical decision-making.

Dynamic Nature of Variant Classification

The continually advancing nature of variant classification represents both a limitation and a strength of genetic testing in HCM. It is a limitation because cardiologists must understand (and communicate to patients) that genetic results are not static, which makes counselling and long-term follow-up more complex and requires periodic reinterpretation requests. However, it is also a strength, particularly for VUS, given that ongoing reassessment may ultimately enable reclassification as either LP/P or likely benign/benign, transforming an inconclusive result into clinically actionable information.

Importantly, although reclassification most often concerns VUS, it can occasionally affect variants initially reported as LP/P, particularly when the supporting evidence is limited. General cardiologists should therefore be aware that even positive results are not invariably definitive, while recognising that well-established LP/P variants with strong evidence are far less likely to change.

Reclassifications may result from a variety of accumulating evidence sources, such as updates in population databases, segregation analysis within families (please refer to the Who Should Be Tested? section for more information), new clinical observations in patients or families identified through sequencing laboratories, published literature, or international data-sharing platforms (e.g. ClinVar, disease-specific registries). Additional contributors include novel functional assays, RNA-based studies, improved in silico prediction tools and advances in variant interpretation frameworks, such as gene-specific guidelines developed by ClinGen expert panels.23 While some research strategies, such as high-throughput functional assays (e.g. multiplexed assays of variant effect [MAVEs] or RNA analyses) are not yet broadly implemented in clinical practice, cardiologists can actively help reduce uncertainty by contributing detailed phenotypic data and facilitating family-based studies.27,28

In summary, the dynamic nature of variant classification highlights the need for periodic re-evaluation of genetic findings. Although laboratories are increasingly offering reinterpretation services, the treating physician plays a key role in initiating these re-evaluations and ensuring that patients are aware of the evolving nature of their genetic results.

Who Should Be Tested?

In cardiovascular genetic disorders, the ‘unit of care’ extends beyond the patient to include their family. Clinical evaluation of both the patient and their relatives is crucial to identify the proband: the most severely affected family member or the one with the earliest disease onset. This assessment helps determine the likely mode of inheritance and guides genetic testing. If HCM is suspected, genetic testing should be offered to the family, starting with the proband. Notably, the absence of a family history does not exclude a genetic aetiology.

If an LP/P variant is identified in the proband, cascade genetic screening should be performed in first-degree relatives. Cascade screening involves testing family members specifically for the LP/P variant identified in the proband, whether or not they show signs of disease. A negative result in a relative (meaning that they do not carry the familial variant) provides reassurance and eliminates the need for ongoing clinical surveillance. Conversely, those who test positive require regular monitoring for potential HCM manifestations. It is important to consider incomplete penetrance, meaning that not all individuals with an LP/P variant will develop the disease, when interpreting results.

It is important to distinguish cascade screening from segregation analysis. While cascade screening applies when an LP/P variant has been identified in the proband, segregation analysis is performed when a VUS is detected. This process involves testing other family members to check whether those who have the genetic variant also show signs of the disease. If the variant is consistently found in affected relatives and absent in healthy ones, it provides stronger evidence that the variant may be disease-causing. The goal is to gather evidence that may help reclassify the VUS as either LP/P or benign, but it is not a diagnostic test. Due to the high prevalence of VUS in genetic reports, selection of the appropriate variant and family members for segregation analysis requires expert clinical and genetic evaluation, which is beyond the scope of this review. Regular clinical follow-up remains necessary for all at-risk relatives when genetic results are inconclusive.

As previously mentioned, a negative genetic test does not rule out a hereditary disorder. First-degree relatives of affected individuals should continue regular clinical evaluations, given that the negative predictive value of genetic tests remains uncertain due to evolving genetic knowledge. Additionally, genetic testing in probands should be periodically reassessed as new pathogenic variants and updated classification criteria emerge.

How to Test?

Selection of the appropriate genetic test can be challenging for clinicians managing HCM. As a genetically heterogeneous condition, HCM remains primarily a clinical diagnosis, with genetic testing serving as a confirmatory tool rather than a definitive diagnostic method.

For the proband, multigene panels using NGS are the most widely used approach due to their cost-effectiveness and good clinical sensitivity. These panels enable simultaneous analysis of multiple genes, eliminating the need to predict the causative gene in each individual. However, not all panels are created equal: their gene content, coverage and technical specifications can vary significantly between laboratories.

When ordering or interpreting genetic tests for HCM, cardiologists should consider key factors:

  • Panel comprehensiveness: ensuring that it includes updated actionable HCM-related genes based on current knowledge. Genetic panels are dynamic, with genes being added as new evidence emerges. For example, the recent ClinGen curation has incorporated updates that refine which genes are considered definitively associated with HCM (refer to the following section for more detailed information).
  • Non-coding region coverage: particularly relevant for genes such as MYBPC3.
  • Copy number variation (CNV) detection: given that large genomic rearrangements may be missed by standard sequencing.

For more information on non-coding regions and CNV, refer to the section ‘Gene-elusive’ Hypertrophic Cardiomyopathy: Where to Look.

Furthermore, sequencing quality and coverage metrics should be reviewed to confirm the technical robustness of the results. If concerns arise, clinicians should consult the testing laboratory regarding potential gaps in analysis.

For relatives, the diagnostic strategy differs. In the context of cascade screening or segregation analysis, testing should be limited to the specific variant previously identified in the proband. This targeted testing is typically performed using Sanger sequencing, which is reliable, cost-effective and appropriate for this purpose.

Hypertrophic Cardiomyopathy-related Genes

While HCM is primarily associated with causative variants in core sarcomeric genes, recent studies indicate that minor structural and regulatory genes also contribute to the genetic aetiology, accounting for approximately 5–10% of positive cases.29–32

This genetic heterogeneity, in which different genes can cause the same phenotype, highlights the complexity of cardiomyopathies. Additionally, phenotypic heterogeneity is also evident: different pathogenic variants in the same gene can lead to distinct clinical presentations, and even the same disease-causing variant may manifest variably in a family. This variability explains why some genetic panels include a broad range of genes or why certain genes appear in multiple phenotype-specific genetic panels.

‘Classic’ Sarcomeric HCM Genes: Those Included in Every HCM Genetic Panel

HCM is often described as an exclusive disease of the cardiac sarcomere, the basic unit of striated muscle, with pathogenic variants detected in most of the major proteins involved in generating or regulating cardiomyocyte contraction (Figure 1). These pathogenic variants, affecting genes encoding sarcomere proteins, are the most frequent and characteristic causes of HCM, given that the sarcomere is the fundamental contractile unit of the heart. Most pathogenic variants exhibit an autosomal dominant inheritance pattern with incomplete penetrance that is age-dependent.

Major sarcomeric gene variants have been associated with HCM, dilated (DCM), LV non-compaction (LVNC) or restrictive (RCM) cardiomyopathy, although each has distinct characteristics. For instance, MYBPC3 pathogenic variants rarely present as DCM or RCM unless additional factors are involved. Conversely, while HCM is the predominant phenotype associated with MYH7 (β-myosin heavy chain) and TNNI3 (cardiac troponin I) pathogenic variants, specific variants in these genes are known to cause DCM or RCM in heterozygous individuals. Moreover, the same genetic variant can produce variable clinical manifestations (HCM or DCM) within the same family, probably due to disease progression or modifying factors.

Figure 1: Cardiac Sarcomere Architecture and Associated Proteins

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Thick Filament Genes

The most frequently implicated genes in HCM pathogenesis are MYBPC3 and MYH7, which encode key components of the sarcomere thick filament: β-myosin heavy chain and myosin-binding protein C, respectively (Figure 1A). Together, these genes account for approximately 75% of all HCM cases with a positive genetic test result, with MYBPC3 being the single most common cause, responsible for around 50% of cases (Figure 2).

MYBPC3

The majority of pathogenic variants in MYBPC3 are truncating variants (nonsense, frameshift, splice-site, start-loss and structural variants), which lead to haploinsufficiency through allelic loss-of-function. Missense pathogenic variants are less common (accounting for less than 20% of all MYBPC3 variants) and primarily affect key residues involved in the structural integrity or function of the protein. Data from the Sarcomeric Human Cardiomyopathy Registry (ShaRe) indicate no significant differences in disease expression and prognosis between pathogenic missense and truncating variants in MYBPC3.13 Historically, pathogenic variants in this gene have been considered to have a milder clinical impact compared with those in other sarcomeric genes, typically associated with a later disease onset and a better prognosis. However, there are cases of early disease expression, severe hypertrophy and high SCD risk, in which additional genetic modifiers have been identified as contributors to adverse outcomes. This variability, also observed in families carrying truncating variants, suggests a role for both genetic and non-genetic modifiers in disease expression.13,33 In any case, clinical risk predictors are generally reliable for pathogenic variants in this gene, given that severe phenotypes and recognised risk markers correlate with adverse events.

MYH7

This is a relatively large and pleomorphic protein, consisting of functionally distinct domains, and it plays a critical role in sarcomere contraction. Most of the disease-causing variants identified are missense, with the majority occurring in the motor domain in the protein’s head region.14 Due to its high pathogenic potential, ClinGen Criteria Specification (CSpec) Registry currently recognise the 167–931-residue region as a mutational hotspot, where novel missense variants are more likely to be disease-causing than those occurring elsewhere in the protein.34

MYH7 pathogenic variants are typically associated with classic HCM. However, they have also been linked to DCM and LVNC, either in isolation or as overlapping phenotypes evolving from HCM. Less commonly, specific MYH7 disease-causing variants have been associated with congenital heart defects such as Ebstein’s anomaly and skeletal myopathies.35–37

Some studies suggest that MYH7-associated HCM carries a worse prognosis than MYBPC3, particularly concerning HF outcomes.9 Data from SHaRe indicate that individuals who are genotype positive for an MYH7 variant have a significantly higher risk of AF and progression to advanced HF, including the need for LV assist device implantation or heart transplantation.9

Clinical expression varies widely depending on the specific pathogenic variant and affected domain. Some variants within specific regions, such as the converter domain (involved in mechanical force transmission), have been associated with more adverse outcomes, including increased arrhythmic risk and progression to HF.15

Other Minor Contributors

Pathogenic variants in other genes encoding myosin regulatory (MYL2) and essential (MYL3) light chains, also part of the thick filament, contribute to HCM but account for a smaller percentage (<1%) of cases.

Thin Filament Genes

Thin filament genes (Figure 1A), which play essential roles in initiating and regulating myocardial contraction, are the next most frequently implicated group.38 These genes encode for cardiac troponins (T, I and C), tropomyosin and actin. Collectively, they are responsible for approximately 10% of genotype-positive HCM cases.

TNNT2

TNNT2 encodes cardiac troponin T, a protein essential for assembling the troponin–tropomyosin complex into actin filaments. Pathogenic variants in this gene are predominantly missense, with HCM being the most prevalent phenotype (~80%), followed by DCM. Disease-causing variants are distributed heterogeneously along the protein, with specific clusters linked to distinct disease expressions. Similar to the case of MYH7, ClinGen CSpec Registry recognises the 89–189-residue region (referred to the MANE [matched annotation from the National Center for Biotechnology Information and the European Molecular Biology Laboratory-European Bioinformatics Institute] Select transcript ENST00000656932.1/NM_001276345.2) as a mutational hotspot.39

In genotype-positive individuals with pathogenic TNNT2 variants, hypertrophy is often mild, but there is a notable discrepancy between LV wall thickness and the extent of myocyte disarray, leading to an increased risk of malignant arrhythmias in some particular variants.40–42 This mismatch suggests that current risk models, which rely heavily on LV thickness as an independent predictor, may underestimate the risk of SCD in genotype-positive individuals with high-risk TNNT2 variants. It is also important to note, however, that not all TNNT2 variants share these characteristics, and some are instead associated with milder phenotypes and a lower event rate.17

TNNI3

This gene encodes the inhibitory subunit of the troponin complex, preventing myosin–actin binding in diastole. Although the majority (~80%) of TNNI3 pathogenic variants cause typical HCM, a significant subset is associated with primary RCM or an overlapping HCM/RCM phenotype. Less frequently (~5%), these variants may result in a DCM-like presentation.43–45 Similar to TNNT2, the vast majority of described disease-causing variants in TNNI3 are missense and tend to cluster in specific regions, currently recognised by ClinGen CSpec Registry as codons 141–209.46 Additionally, there is also a notable dissociation between the degree of ventricular hypertrophy and the risk of complications, particularly SCD, in which case, the use of the HCM SCD risk calculator might not be completely accurate.

TNNC1

Pathogenic variants of TNNC1 are rare but have been linked to both HCM and DCM. Disease-causing variants of this gene affect calcium binding and troponin complex function, leading to altered contractile regulation. While their contribution to cardiomyopathy is less well defined, TNNC1 variants have been implicated in both hypertrophic and dilated phenotypes, some associated with a higher risk of arrhythmic events.47–49

TPM1

This gene encodes α-tropomyosin, a sarcomere protein essential for actin–myosin interactions in response to intracellular calcium concentration. Disease-causing variants in TPM1 are thought to account for a small proportion of both sporadic and familial genotype-positive HCM cases (1–5%).50 This gene represents one of the clearest examples of extreme intra- and interfamilial variability, with significant phenotype heterogeneity among individuals carrying the same variant.51 Some pathogenic variants have been associated with increased arrhythmic risk, while others show a relatively benign course.52 Given this variability, precise genotype–phenotype correlation remains an active area of investigation.

ACTC1

Cardiac α-actin is encoded by the ACTC1 gene. Pathogenic variants have been implicated in HCM, DCM, LVNC, septal defects and early-onset atrial arrhythmias.53–55 Given the essential function of actin in sarcomere integrity, most pathogenic variants in this gene are highly deleterious, typically leading to significant disruption in myocardial architecture and function, although they account for only ~1% of HCM cases. Although ACTC1 variants are rare, they should be considered in cases of complex phenotypes involving both cardiomyopathy and structural defects. Furthermore, ACTC1 has a highly conserved sequence with low variability tolerance; a novel undescribed variant therefore has a high probability of causing disease.56

Less Prevalent Regulatory and Structural Genes Associated with HCM: Those that Should be Included in the Requested Genetic Panel

While pathogenic variants in core sarcomeric genes account for most genetically confirmed HCM cases, a subset of non-sarcomeric genes has also been implicated in disease pathogenesis because they also play a key role in sarcomere function. These genes encode proteins involved in cytoskeletal organisation, calcium homeostasis and protein turnover, expanding the genetic architecture of HCM beyond the sarcomere (Figure 1B). Many genes involved in this complex network have been explored and proposed as candidates in the study of HCM. Relatively few genes have a proven association with the phenotype. This section presents those genes with sufficient evidence to be considered causal for HCM.

FHOD3

This gene has emerged as one of the most relevant genes with a clear dominant inheritance pattern. It encodes a formin homology protein that regulates actin polymerisation, playing a fundamental role in maintaining sarcomere structure. Pathogenic missense variants, particularly those clustering in the coiled-coil domain (residues 622–655) and the segment near p.Ser527 and p.Tyr528, have been linked to HCM.31,57 These variants show incomplete penetrance and a predominantly late-onset phenotype, often after 40 years of age in men and 55 in women. Some affected individuals also have ventricular hypertrabeculation, a trait less commonly seen in sarcomere-driven HCM. Truncating variants in FHOD3 remain of uncertain significance, given that no strong evidence supports their direct contribution to disease.

Other genes with dominant inheritance related to several structural components, particularly those involved in Z-disk integrity, have been linked to HCM, albeit with lower frequencies:

JPH2

This gene encodes junctophilin-2, a protein involved in the interaction of L-type calcium channels on the plasma membrane and ryanodine receptor type 2 in the sarcoplasmic reticulum. Pathogenic variants (to date, few reported variants, mostly missense) in this gene are associated with HCM, often accompanied by conduction abnormalities and AF.58

ACTN2

This gene, encoding α-actinin 2, is a crucial Z-disk protein that anchors the contractile machinery. Pathogenic variants in ACTN2 have been reported in patients with HCM, DCM, LVNC and RCM.59–62 The cardiomyopathy reported in families carrying ACTN2 variants does not fit well into the classical categories of HCM or DCM. Individuals can show variable combinations of hypertrophy, dilatation and hyper/hypocontractility, and the phenotype can vary between individuals in the same family. Most of the variants described are missense, but also some loss-of-function (nonsense and frameshift) variants have been associated with the mentioned phenotypes.

FLNC

This gene encodes filamin-C (or γ-filamin), a muscle-specific cytoplasm protein involved in the reorganisation of the actin cytoskeleton in response to signalling events. Pathogenic variants in this gene were initially associated with LV arrhythmogenic cardiomyopathy (ACM) (loss-of-function variants), skeletal myopathy and RCM (specific missense variants). Additional missense variants were described in association with HCM.63, 64 Currently, ClinGen classifies FLNC as definitively associated with myofibrillar myopathy and places it under syndromic increased wall thickness, which may present in isolation or as part of a broader phenotype, potentially mimicking sarcomeric HCM.65 In the majority of the cases the hypertrophic phenotype is mild and presentation is late-onset; however, other studies have reported more severe outcomes.66 Because of its substantial size, identification of missense FLNC variants in high-throughput sequencing studies is commonplace. The presence of restrictive physiology may offer supportive evidence, but in most cases determining the pathogenicity of a novel non-truncating variant in a patient with HCM is challenging.

PLN

Phospholamban, encoded by PLN, is a protein that regulates calcium reuptake by the sarcoplasmic reticulum. Pathogenic variants have been associated with a form of ACM/DCM and rarely with null-type variants in simple heterozygosis and incomplete penetrance to HCM.67 PLN is a very small gene (with a single coding exon), hence few variants have been identified, and its expected contribution to HCM is low (<1%).

Additional minor genes show other modes of inheritance: semi-dominant or recessive forms. Semi-dominance includes both dominant and recessive inheritance patterns in which individuals with heterozygous variants have an intermediate phenotype and individuals with homozygous variants have a more severe phenotype and/or earlier onset. Although genes such as ALPK3 fit this definition, ClinGen currently recognises CSRP3 as the only gene associated with a semi-dominant inheritance pattern in HCM.65

Notably, biallelic deleterious variants in core sarcomere genes, such as MYBPC3 and MYH7, have also been consistently associated with markedly more severe phenotypes and early-onset cardiomyopathy.68-70 Nevertheless, based on current evidence, these sarcomeric biallelic forms appear to result in more severe disease than biallelic variants found in genes classified as semi-dominant. In particular, biallelic involvement of sarcomere genes often leads to early-onset, rapidly progressive cardiomyopathy, with significant clinical consequences frequently manifesting during infancy or early childhood.71

ALPK3

This gene encodes α-protein kinase 3, a nuclear protein with transferase and protein kinase activity, which functions to aid in myosin-mediated force buffering and sarcomere proteostasis. It is also considered to play an essential role in the early differentiation of cardiomyocytes. The association of ALPK3 with autosomal dominant HCM has been relatively recently described, but it is sufficient to be classified as strong.30,65,72,73 All of the variants associated with HCM in simple heterozygosity are null type (nonsense, frameshift and splice site). Additionally, pathogenic variants affecting both alleles of the gene are associated with the development of paediatric-onset cardiomyopathy (HCM and DCM), with Noonan-like syndromic traits (e.g. musculoskeletal and dysmorphologic) in >80% of the cases, and with prolonged QT interval in more than 50%.74–76 Most of the autosomal recessive patients harboured a null ALPK3 variant, but missense variants are described (compound heterozygosis with a loss-of-function or in homozygosis).

CSRP3

This gene encodes the cysteine-rich cardiac LIM protein, a key structural component of the Z-disc. Pathogenic variants in this gene, primarily missense, have been consistently associated with HCM, supported by familial segregation, enrichment and functional evidence.77 Monoallelic missense disease-causing variants, such as p.(Cys150Tyr), have been linked to late-onset disease, incomplete penetrance and relatively mild phenotypes, both in terms of hypertrophy severity and adverse outcomes.78–81 The semi-dominant classification of CSRP3 is further supported by reports of biallelic truncating variants in addition to the well-characterised monoallelic missense variants.82,83

TRIM63

This gene, encoding an E3 ubiquitin ligase responsible for sarcomere protein turnover, is one of the best-characterised recessive HCM genes. Biallelic loss-of-function variants have been linked to a specific phenotype of concentric hypertrophy with a high incidence of systolic dysfunction.32 More recently, it has been suggested that heterozygous truncating variants in TRIM63 might also predispose to HCM, raising the possibility of semi-dominance.84 Data from our group cohort have not confirmed this signal, emphasising the need for further studies to establish whether monoallelic loss-of-function variants in TRIM63 contribute to disease risk.

SVIL

This gene encodes supervillin, a cytoskeletal protein involved in myofibril organisation. It has been recently associated with HCM in a large genome-wide association study (GWAS).85 Rare truncating SVIL variants were found to be enriched in cases of HCM, with a 10-fold increased risk, suggesting a disease model in which heterozygous carriers are predisposed to a milder phenotype, while biallelic variants may cause a more severe presentation.86 Although its precise role remains to be fully characterised, SVIL appears to function similarly to ALPK3, reinforcing the idea that certain genes do not fit neatly into classic dominant or recessive inheritance patterns.

KLHL24

Fully recessive forms of HCM remain rare, but KLHL24 is one such example. Biallelic loss-of-function variants in this gene lead to early-onset hypertrophy with frequent arrhythmic complications.87 Unlike semi-dominant genes, heterozygous KLHL24 carriers do not have increased disease risk, supporting its classification as a purely recessive gene.

A recent reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel (HCVD GCEP) has refined the list of genes definitively associated with HCM, incorporating both new genes and re-evaluating previously curated ones.65 Among these, FHOD3 was newly classified as definitive, and KLHL24 and MT-TI reached a moderate level of evidence. Additionally, TRIM63 was found to have a strong autosomal recessive inheritance pattern, while CSRP3 was upgraded to definitive with a semi-dominant mode of inheritance. These updates underscore the increasing recognition of non-sarcomeric contributions to HCM. The relevance of these non-sarcomeric genes has also been observed in our own cohort (Figure 2).6

Given these findings, ClinGen now recommends including these genes in genetic testing panels for HCM, aligning with the evolving understanding of its genetic architecture. As precision medicine advances, the integration of non-sarcomeric genes into routine clinical practice is likely to improve patient management and individualised care.

Figure 2: Genetic Testing Results in 14,026 Probands with Hypertrophic Cardiomyopathy

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Hypertrophic Phenotypes Secondary to Phenocopies: Genes Usually Included in the HCM Genetic Panel

A semantic debate exists (beyond the scope of this review) regarding whether the definition of HCM should include cases of hypertrophy caused by phenocopies, which often present with extracardiac and syndromic features. For practical purposes we will refer to these conditions as ‘hypertrophic phenotypes secondary to phenocopies’, although the distinction from classic HCM is not always clear. Notably, some of these conditions exhibit hypertrophy as their primary, and sometimes nearly exclusive, clinical manifestation. The genetic causes underlying these phenotypes are often included in standard HCM gene panels.

The vast majority of these heterogeneous rare diseases, commonly called phenocopies, are systemic and inherited. Some patients present with subtle extracardiac features, making it easy for clinicians to overlook the true aetiology of their hypertrophic phenotype.

These conditions arise from diverse non-sarcomeric mechanisms, including:

  • metabolic disorders (e.g. lysosomal and glycogen storage diseases);
  • RASopathies (RAS-MAPK pathway disorders);
  • myocardial infiltration or inflammation (e.g. cardiac amyloidosis);
  • mitochondrial diseases; and
  • neuromuscular syndromes (e.g. Friedreich’s ataxia, desminopathies).

Differentiating phenocopies from sarcomeric HCM can be challenging, underscoring the critical role of genetic testing. These conditions should be considered and thought of as a second-tier evaluation once a basic HCM panel has been performed and the result is negative; however, in the presence of clinical suspicion or red flags, a broader panel may be justified as a first-line approach. An accurate diagnosis is essential, given that these conditions differ significantly in prognosis, disease-specific treatments are increasingly available, and standard SCD risk calculators are not applicable to these HCM subtypes. Table 1 summarises these heterogeneous diseases and their implicated genes.

Table 1: Genes Associated with Hypertrophic Phenotypes Secondary to Genocopies

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‘Gene-elusive’ Hypertrophic Cardiomyopathy: Where to Look

As previously mentioned, despite advances in genetic testing, a significant proportion of patients diagnosed with HCM receive a negative genetic result, meaning that no LP/P variant is identified, even after a comprehensive and well-conducted analysis (Figure 2A).6

Several possible explanations exist for these unresolved cases. Some may be attributed to large genomic rearrangements, such as CNVs, which escape detection by standard sequencing methods. Others may involve non-coding variants, particularly those in deep intronic regions or regulatory elements, which are not routinely covered by conventional gene panels. Additionally, increasing evidence suggests that HCM is not always a monogenic disease; in many cases its manifestation may result from complex polygenic inheritance or gene–environment interactions.

These three possibilities: CNVs, non-coding variants and non-Mendelian inheritance, represent key areas of ongoing research and potential directions for future genetic exploration in HCM. Notably, both CNVs and non-coding variants are particularly relevant in the context of MYBPC3, the primary haploinsufficient gene in HCM.

Non-coding Variants in Hypertrophic Cardiomyopathy

Most genetic studies in HCM focus on coding regions, even though non-coding sequences (comprising ~97% of the human genome) play a critical role in gene regulation, splicing and chromatin organisation. Increasing evidence suggests that non-coding variants contribute to genotype-negative HCM, particularly in genes that do not tolerate haploinsufficiency, such as MYBPC3.

While intronic variants in other sarcomeric genes remain under investigation, MYH7 and others appear to be less susceptible to haploinsufficiency-related mechanisms.

The strongest evidence linking non-coding variants to HCM involves deep intronic variants in MYBPC3.88–91 Some of these can disrupt splicing (even located more than 100 base pairs away from canonical exon-intron sites), leading to aberrant transcripts and haploinsufficiency.

When considering non-coding variants, two critical challenges arise:

  • Coverage limitations: deep intronic variants far from canonical splice sites are not captured by conventional NGS panels or whole exome sequencing, which focus on exonic and exon–intron boundary regions.
  • Predictive limitations: bioinformatic tools often fail to accurately classify these variants. A well-documented example is c.3331-26T>G, initially predicted as benign but later confirmed to cause abnormal splicing in a Spanish family.89

Until bioinformatic predictors improve, functional studies (minigene assays) and RNA sequencing in patient-derived samples are essential for identifying and validating pathogenic non-coding variants. However, these approaches are rarely available in clinical genetic laboratories.

Preliminary data from our cohort suggest that deep intronic MYBPC3 variants may explain 2–3% of unresolved cases (Health in Code, unpublished data). Given this, routine sequencing of at least the deep intronic regions of MYBPC3 should be considered.

Beyond intronic sequences, enhancer and promoter variants regulating cardiac gene expression are emerging as potential contributors to HCM.92

Although direct links remain scarce, future studies integrating epigenomic profiling and single-cell transcriptomics may uncover novel regulatory variants influencing disease susceptibility.

Copy Number Variations in Hypertrophic Cardiomyopathy

The vast majority of pathogenic genetic variants in HCM are point variants or small indels affecting individual nucleotides. However, CNVs (i.e. large genomic deletions or duplications) can also disrupt gene function by removing entire coding exons (haploinsufficiency) or altering gene dosage. While CNVs play a major role in other cardiovascular diseases (e.g. DMD-related cardiomyopathy), their contribution to HCM appears to be limited. As expected, most reported CNVs in HCM involve MYBPC3.

Large deletions and duplications have been described in MYBPC3, but systematic studies suggest a low prevalence (<1%) of clinically relevant CNVs in HCM, with most cases involving multi-exonic or complete gene deletions.92–95 Detection rates are influenced by technical limitations, given that standard NGS is optimised for small variants, whereas CNV analysis typically requires MLPA (multiplex ligation-dependent probe amplification), aCGH (array comparative genomic hybridisation) or single-nucleotide polymorphism (SNP) arrays. Bioinformatic algorithms now enable CNV inference from NGS data, but challenges remain, particularly in repetitive or homologous regions.

Although routine CNV screening in HCM is not widely recommended, bioinformatic detection of CNVs should be standardised as part of NGS analysis to screen for large duplications and deletions. If a CNV is deemed clinically relevant, it should be confirmed using an orthogonal technique for evaluating these structural variants (such as SNP array, MLPA or digital polymerase chain reaction) to ensure diagnostic accuracy. However, it is important to note that not all bioinformatic tools have adequate sensitivity and specificity, therefore results must be interpreted with caution and always in the context of the patient’s pretest probability.

Beyond Monogenic Inheritance: Non-Mendelian Inheritance in HCM

A key challenge in HCM genetics is incomplete penetrance and variable expressivity, underscoring the influence of genetic, environmental and epigenetic factors on disease manifestation. While some cases follow a strict monogenic model, growing evidence suggests that common genetic variants may act as modifiers, either modulating disease severity in individuals with a pathogenic variant or contributing to HCM risk in genotype-negative cases.4,6,85,96,97

Unlike Mendelian inheritance, in which single high-impact variant primarily drives disease susceptibility, complex inheritance arises from the co-inheritance of multiple susceptibility variants.

The genetic landscape of HCM can be visualised as a continuum (Figure 3A). At one extreme are rare, highly penetrant monogenic variants, which cluster within families and follow a clear Mendelian pattern. At the other extreme are common polymorphisms, which individually have minimal impact but, when combined, can influence HCM susceptibility through polygenic mechanisms.

Between these extremes lie intermediate-effect variants (IEVs): genetic variants with higher allele frequencies than expected for a classical Mendelian disorder. These IEVs may contribute to disease either independently or in combination, forming the basis of oligogenic inheritance in HCM. Figure 3B illustrates a real-world example of how such variants contribute to disease expression.6

Figure 3: Genetic Architecture of HCM: A Continuum of Inheritance Patterns

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Oligogenic Inheritance: Intermediate-effect Variants

Oligogenic inheritance refers to cases in which a few rare variants or IEVs contribute to disease risk rather than a single causal variant. The presence of multiple variants in an individual may increase penetrance, modify disease severity or influence phenotype expression, explaining some of the heterogeneity observed in HCM.

Several examples illustrate the potential relevance of oligogenic inheritance in HCM. TNNT2 p.Arg278Cys and MYBPC3 p.Glu441Lys are two IEVs that have been identified in HCM cases but which are also found in population controls at frequencies above what would be expected for a monogenic disorder. Although these variants alone may not be sufficient to cause disease, they could act as modifiers, either by exacerbating hypertrophy in individuals with another pathogenic variant or by subtly increasing disease risk when combined with other genetic or environmental factors.

Recent sequencing studies have identified multiple rare variants in sarcomeric and non-sarcomeric genes in some HCM cases, suggesting a possible cumulative burden model. A recent study by Meisner et al. analysed the impact of low-penetrance sarcomeric variants in a large cohort of HCM patients from SHaRE, demonstrating that these variants can contribute additively to disease risk.98 In that study, variants previously considered of uncertain significance were found to be enriched in HCM cases compared with controls, and their presence in combination with classic monogenic variants was associated with a more severe phenotype. This finding supports the notion that the genetic architecture of HCM cannot be explained solely by a strict Mendelian model but rather involves the interaction of multiple genetic factors.

Our own cohort further highlights the significance of IEVs in HCM.6 Of 14,026 cases, 731 individuals (6.1%) carried IEVs, with 4.7% harbouring them in isolation (Figure 2A). Interestingly, 65.3% of these variants were found in non-sarcomeric genes, suggesting that non-sarcomeric loci play an even greater role in oligogenic inheritance than previously anticipated. The estimated population-attributable fraction for IEVs in our cohort was calculated at 4.9%, underscoring their substantial contribution to HCM heritability. Moreover, these variants appear to influence disease expression, given that individuals with IEVs had a younger median age at diagnosis and increased LV maximum wall thickness compared with genotype-negative patients. When IEVs were present alongside a monogenic variant, the clinical phenotype was more severe than in cases of monogenic variants alone, with earlier disease onset and a higher risk of major adverse cardiac events.

These findings reinforce the importance of considering IEVs when interpreting genetic testing results and suggest that future risk stratification models should incorporate their potential modifying effects. While the precise contribution of oligogenic inheritance remains to be fully established, these findings highlight the need for a broader analytical approach in genetic studies, moving beyond the traditional single-gene paradigm.

Polygenic Inheritance

At the other end of the genetic spectrum, polygenic inheritance involves the combined effect of numerous common variants, each exerting a small but additive influence on disease risk. GWAS have identified multiple SNPs enriched in HCM cases.4,83,96,97 Unlike monogenic variants, these variants are common in the general population and have low individual penetrance, but their cumulative effect can contribute to disease development.

A polygenic framework helps explain why some individuals without a known pathogenic variant still develop HCM. Polygenic risk scores (PRS) quantify an individual’s genetic predisposition by summing the effects of multiple risk-associated SNPs. PRS have been successfully applied in cardiovascular diseases, such as coronary artery disease and AF, and are now being explored in HCM. Preliminary studies suggest that individuals with higher PRS have greater increased LV wall thickness and an increased overall disease risk, even in the absence of a monogenic pathogenic variant.99

A key challenge in polygenic inheritance is determining the threshold at which the cumulative effect of multiple variants becomes clinically significant. While PRS represents a promising tool for assessing HCM susceptibility in genotype-negative cases, further validation is required before it can be incorporated into routine clinical practice.

A recent statement from the American Heart Association on polygenic risk score testing highlights the progress made and how its role in clinical care is likely to evolve over time.100

The continuum of genetic contributions in HCM, ranging from rare Mendelian pathogenic variants to polygenic risk, demonstrates that a single-gene model is insufficient to explain all cases. Integration of oligogenic and polygenic inheritance models will be crucial for refining diagnostic criteria, risk stratification, and personalised management strategies in the coming years.

Conclusion

Genetic testing remains a highly specialised field, primarily within the domain of cardiovascular genetic specialists. However, it is crucial for general cardiologists to have a foundational understanding of genetics, as well as current advancements in the field. This knowledge will enhance their ability to integrate genetic insights into the management of HCM and ultimately improve patient care. Cardiologists should be familiar with the indications for genetic testing and the evolving genetic landscape of cardiovascular diseases, particularly given the prevalence of HCM.

Genetic testing has become a valuable tool in HCM, not only by clarifying the underlying aetiology and enabling family cascade screening, but also by beginning to inform prognosis, all within a framework that can be cost-effective. Still, its clinical utility is tempered by a modest diagnostic yield, the frequent identification of VUS, and the fact that variant interpretation evolves over time, reminding cardiologists that results should be viewed as dynamic rather than definitive.

Our understanding of HCM has advanced significantly over time, driven in large part by progress in genetics. Initially considered a monogenic, sarcomeric disease, HCM is now recognised as a more complex and heterogeneous condition.

While MYH7 and MYBPC3 remain the predominant causal genes in HCM with positive genetic results, recent re-evaluations have highlighted the role of non-sarcomeric genes such as FHOD3, ALPK3, CSRP3 and TRIM63. These findings underscore the need for updated genetic panels that include these newly validated genes, ensuring a more comprehensive diagnostic approach.

Furthermore, the recognition of oligogenic and polygenic contributions to disease pathogenesis has further refined our understanding of HCM, emphasising that its inheritance is more complex than previously assumed.

In addition to these genetic advancements, emerging therapeutic strategies, such as myosin inhibitors and gene replacement therapy, represent a paradigm shift in the management of HCM.101 However, challenges remain, particularly regarding the cost-effectiveness of these novel therapies and their integration into clinical risk models.

Ultimately, the integration of advanced molecular diagnostics, personalised treatment options, and the latest genetic insights is ushering in a new era of HCM management. This shift towards precision medicine promises to tailor both therapeutic and preventive strategies to the unique genetic profile of each patient. Future research will continue to explore unresolved genetic cases, delve deeper into the role of non-coding variants, investigate gene–environment interactions, and assess the impact of IEVs and PRS on disease outcomes.

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