HCM: Genetics and Phenotypes
Detail pages. entities/MYBPC3 · entities/MYH7 · entities/Anderson-Fabry-Disease · concepts/Fabry-Cardiomyopathy · concepts/Danon-Disease
Definition
Hypertrophic cardiomyopathy is the most common monogenic cardiac disorder, affecting approximately 1 in 500 adults. A causal sarcomeric variant is identified in roughly 40–60% of patients, but the remainder are not gene-negative by default: a polygenic contribution is measurable and independent of rare variants, and an overlapping minority have a phenocopy — a different genetic disease that produces the same hypertrophy. Because the phenotype is defined by wall thickness rather than by genotype, the genetics of HCM is really a question of discriminating three populations that look identical on echocardiography: sarcomeric disease, polygenic disease, and mimics. (sources/HCM-NEJM-2025, rating: very high; sources/esc-cmp-2023, rating: very high)
Abbreviations: PRS, polygenic risk score; VUS, variant of uncertain significance; WGS, whole-genome sequencing.
Key Concepts
Genetic Architecture
- Diagnostic yield is contested between sources. Approximately 40–60% of patients have a causal sarcomeric variant identified, with the highest likelihood in young patients and those with familial disease; one major review puts the figure at about 40% of those tested. (sources/esc-cmp-2023, rating: very high; sources/HCM-NEJM-2025, rating: very high)
- The core sarcomeric genes are MYBPC3, the most common, and MYH7, together accounting for about 45% and 35% of gene-positive cases respectively. Also causal: TNNT2, TNNI3, MYL2, MYL3, ACTC1 and TPM1 — at least eight genes in total. (sources/HCM-NEJM-2025; sources/esc-cmp-2023)
- ClinGen gene-disease validity, 2026-05-09. Definitive for HCM: MYBPC3, MYH7, TNNI3, TNNC1, TPM1, FHOD3, CSRP3 (semidominant), ACTC1 and ALPK3 (autosomal recessive definitive, autosomal dominant strong). PLN is definitive for intrinsic cardiomyopathy spanning the hypertrophic–dilated spectrum. (sources/clingen-summary-2026-05-09, rating: high)
- Genes that should not be reported as pathogenic for HCM: CALR3, MYH6, CASQ2, DSP (for HCM specifically), VCL, KCNQ1 and ANKRD1 are all disputed; RYR2 has only limited evidence. Broad legacy panels may therefore return false-positive results. See concepts/ClinGen-Gene-Disease-Validity. (sources/clingen-summary-2026-05-09)
- MYBPC3 mutation burden. More than 350 individual MYBPC3 mutations are described, over 60% of them truncating. Most heterozygous carriers have late onset and benign progression. Bi-allelic truncating mutations — homozygotes or compound heterozygotes — cause fatal neonatal cardiomyopathy with death within the first year, for which transplantation is the only curative option. Compound variants account for 14% of childhood-onset HCM. (sources/mybpc3-gene-2015, rating: medium)
- The South Asian founder variant. A 25-bp deletion in MYBPC3 intron 32 is carried by 4% of the South Asian population and confers a 6.99-fold increase in heart failure risk, which materially raises pre-test probability in South Asian patients with unexplained cardiomyopathy. (sources/mybpc3-gene-2015)
- Regional founder mutations raise the risk of compound heterozygosity: Iceland 58% of HCM, Veneto 19.5%, the Netherlands, Finland and Japan around 16–17% each, Tuscany 14%, and centre-east France 8.4%. (sources/mybpc3-gene-2015)
Polygenic Risk
- Common-variant loci outside the sarcomere have been associated with HCM at FHOD3, ALPK3, PLN, ACTN2 and CSRP3 — implicating calcium handling and actin cytoskeletal organisation as polygenic contributors. (sources/gwas-arrhythmias-cmp-genes-2025, rating: high)
- A multi-ancestry PRS confers an odds ratio of 2.34 per standard deviation for HCM case status. The effect is independent of sarcomeric variant carrier status, so a patient without an identifiable pathogenic rare variant can still carry substantially elevated inherited risk. The PRS also predicts death and clinical progression. (sources/gwas-arrhythmias-cmp-genes-2025)
- Several loci act in opposite directions in HCM and dilated cardiomyopathy — the same allele that raises HCM risk lowers dilated cardiomyopathy risk at MYBPC3, ALPK3 and FHOD3. The two diseases therefore sit at opposing ends of a single contractility axis, and cardiac myosin inhibition acts on that axis from the hypertrophic side. See concepts/GWAS-Cardiac-Genetics and entities/DCM. (sources/gwas-arrhythmias-cmp-genes-2025)
Phenocopies and Genocopies
- Genocopies that clinically resemble HCM but require different management: Anderson–Fabry disease (GLA), transthyretin amyloidosis (TTR), the glycogen storage disorders Danon (LAMP2), Pompe (GAA) and PRKAG2, the RASopathies (PTPN11, RAF1), and Friedreich ataxia (FXN). Together they account for under 5% of adult disease but up to 25% of childhood cases. Hereditary amyloidosis, Andersen syndrome and other glycogen storage diseases are further mimics. (sources/esc-cmp-2023, rating: very high; sources/HCM-NEJM-2025, rating: very high)
- The three that change management most. Fabry disease is treatable with enzyme replacement or chaperone therapy, and its cardiac phenotype is covered on concepts/Fabry-Cardiomyopathy; Danon disease progresses to transplantation in early adulthood and is the subject of AAV gene replacement on concepts/Danon-Disease; transthyretin amyloidosis has its own disease-modifying therapies and should be excluded before a diagnosis of sarcomeric disease is accepted. See entities/ATTR-Amyloidosis.
- HCM is the commonest cardiomyopathy phenotype in mitochondrial disease. Obstructive physiology is rare, presentation may be antenatal, and progression to a dilated phenotype with systolic dysfunction occurs. (sources/mitochondrial-cv-aha-2025, rating: very high)
- Mitochondrial syndromes to recognise: MELAS and MIDD (m.3243A>G, the latter at lower variant allele fraction), MERRF (m.8344A>G), Leber hereditary optic neuropathy, Leigh syndrome and Pearson syndrome. See concepts/Mitochondrial-Cardiomyopathy and concepts/Heteroplasmy. (sources/mitochondrial-cv-aha-2025)
- Standard cardiomyopathy and arrhythmia panels do not include mitochondrial genes, neither mitochondrial DNA nor nuclear-encoded mitochondrial genes. Mitochondrial HCM therefore returns a "gene-elusive" result on routine testing — a systematic false negative rather than a true negative. (sources/mitochondrial-cv-aha-2025)
- Suspect mitochondrial disease when HCM presents with maternal inheritance, multisystem features (neurological, ophthalmological, hearing loss, diabetes), elevated serum lactate, or no sarcomeric variant on a standard panel. Whole-genome sequencing, not a targeted panel, is first-line in this setting, with counselling for non-Mendelian inheritance. (sources/mitochondrial-cv-aha-2025)
Contradictions / Open Questions
- ClinGen has reclassified seven genes that older literature and panels treat as HCM genes. CALR3, MYH6, CASQ2, DSP, VCL, KCNQ1 and ANKRD1 are disputed for HCM; only RYR2 retains limited evidence. The DSP dispute applies to isolated HCM without the woolly hair and keratoderma phenotype, for which DSP retains definitive arrhythmogenic cardiomyopathy evidence. Clinicians using legacy panels may be acting on false-positive results. (sources/clingen-summary-2026-05-09, rating: high)
- The reported diagnostic yield is not stable across sources. ESC 2023 gives 40–60% of patients; the 2025 NEJM review gives about 40% of those tested. The two figures may reflect different denominators — all patients versus those actually tested — but neither document says so, and the difference matters when counselling a family about the probability of a negative result. (sources/esc-cmp-2023, rating: very high; sources/HCM-NEJM-2025, rating: very high)
- PRS independence from rare variants complicates cascade screening. Because a high polygenic score raises risk in people who test negative for a pathogenic sarcomeric variant, a negative family cascade result is not the same as low risk. Neither the ESC nor the AHA/ACC guideline incorporates a PRS into family screening, so a recognised risk signal sits outside every recommended pathway. (sources/gwas-arrhythmias-cmp-genes-2025, rating: high)
- Mitochondrial HCM is invisible to standard testing. Because neither mitochondrial DNA nor nuclear-encoded mitochondrial genes are on routine panels, a "gene-elusive" HCM result is compatible with mitochondrial disease. The correct next step is whole-genome sequencing on clinical suspicion, but no guideline defines how aggressively to pursue it, and the phenotype overlap with sarcomeric disease is broad. (sources/mitochondrial-cv-aha-2025, rating: very high)
- Phenocopy prevalence is quoted in two incompatible ways. Genocopies are described as under 5% of adult disease but up to 25% of childhood disease, and mitochondrial disease is described separately as the commonest cardiomyopathy phenotype in mitochondrial disorders without any population denominator. A clinician deciding how hard to look for a mimic has no single estimate of prior probability to work from. (sources/esc-cmp-2023; sources/mitochondrial-cv-aha-2025)
Connections
- Part of entities/HCM — the parent overview
- The mechanism these variants produce — concepts/HCM-Mechanism
- How the phenotype is diagnosed and risk assessed — concepts/HCM-Diagnosis-and-Risk
- Treatment — concepts/HCM-Management
- Gene pages — entities/MYBPC3 and entities/MYH7
- Protein and cellular biology — concepts/Sarcomere-Biology and concepts/Haploinsufficiency
- Gene-disease curation — concepts/ClinGen-Gene-Disease-Validity and concepts/Variant-Reclassification
- Common-variant genetics — concepts/GWAS-Cardiac-Genetics and concepts/Polygenic-Risk-Score
- Phenocopies — concepts/Fabry-Cardiomyopathy, entities/Anderson-Fabry-Disease, concepts/Danon-Disease, entities/ATTR-Amyloidosis, concepts/Mitochondrial-Cardiomyopathy and concepts/Heteroplasmy
- Testing and family follow-up — concepts/Genetic-Testing-in-Cardiomyopathy and concepts/Cascade-Family-Screening