Hypertrophic cardiomyopathy (HCM)

It has a prevalence of approximately 1:500 in the Caucasian population.

Although hypertrophic cardiomyopathy (HCM) is most commonly inherited in an autosomal‑dominant manner, its genetic architecture is more complex, as penetrance and expressivity vary widely, and numerous syndromic or metabolic conditions often following autosomal‑recessive or X‑linked inheritance can present with an HCM phenotype.

Overall, causative variants can currently be identified in approximately 60% of all HCM cases in routine diagnostics.

The differential diagnosis of hypertrophic cardiomyopathy (HCM) is broad, as numerous metabolic, mitochondrial, infiltrative, storage and syndromic conditions can present with a hypertrophic phenotype, including , cardiac amyloidosis, glycogen storage disorders (e.g., ), , and such as , alongside additional phenocopies like infiltrative or endocrine diseases. Therefore, particularly in children or in patients with atypical features, it is essential to assess for extracardiac manifestations such as dysmorphic features, developmental delay, neuromuscular signs, metabolic abnormalities or systemic organ involvement. Modern genetic testing panels therefore evaluate both the primary HCM gene set and genes associated with syndromal disorders that feature HCM as part of a wider phenotype with different therapeutic and prognostic implications identified early.

• In patients with hypertrophic cardiomyopathy (HCM), molecular genetic testing is an important component of the diagnostic work-up, particularly in familial disease, early-onset presentations, unexplained left ventricular hypertrophy, or when clinical features suggest a syndromic, metabolic, or storage disorder. According to the , genetic testing accompanied by genetic counselling is recommended as part of the clinical evaluation in patients with cardiomyopathy (Class I, Level of Evidence B).
• A confirmed molecular diagnosis can increase diagnostic certainty, identify the underlying aetiology, and help distinguish sarcomeric HCM from important phenocopies such as Fabry disease, amyloidosis, PRKAG2 syndrome, Danon disease, or RASopathies, which may require distinct surveillance and treatment strategies. Pathogenic variants in sarcomeric genes, particularly MYH7, MYBPC3, TNNT2, and TNNI3, account for most genotype-positive cases of non-syndromic HCM.
• Genetic results are especially relevant for family management. Once a pathogenic or likely pathogenic germline variant has been identified in the index patient, targeted cascade testing can be offered to at-risk relatives. Due to the typically age-dependent and often later manifestation of HCM, predictive genetic testing in clinically unaffected children is generally recommended from around the age of 10 years, unless earlier testing is indicated by childhood-onset disease in the family, symptoms, a malignant family history, or planned participation in intensive competitive sports. Genotype-positive relatives can enter structured cardiac surveillance for early detection of disease expression, whereas genotype-negative relatives can often be discharged from long-term cardiological follow-up for that familial variant.
• Although genotype may provide prognostic information in selected cases, clinical risk assessment in HCM remains primarily based on phenotype, family history, symptoms, ECG findings, imaging, arrhythmia burden, and established sudden cardiac death risk models. Genetic findings should therefore be integrated into the broader clinical context rather than interpreted in isolation.

• Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503-3626. doi:10.1093/eurheartj/ehad194. PMID:.
• Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, et al. Reassessment of Mendelian gene pathogenicity using 7855 cardiomyopathy cases and 60706 reference samples. Genet Med. 2017;19(2):192-203. doi:10.1038/gim.2016.90. PMID:.
• Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J. 2014;35(39):2733-79. doi:10.1093/eurheartj/ehu284. PMID:.
• Lopes LR, Syrris P, Guttmann OP, O’Mahony C, Tang HC, Dalageorgou C, et al. Novel genotype-phenotype associations in hypertrophic cardiomyopathy: insights from a large study of clinically affected families. J Med Genet. 2013;50(4):228-38. doi:10.1136/jmedgenet-2012-101270. PMID:.
• Cirino AL, Channaoui N, Ho C. Nonsyndromic hypertrophic cardiomyopathy overview. 2025 Mar 6. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301725.
• Ommen SR, Ho CY, Asif IM, Balaji S, Burke MA, Day SM, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the management of hypertrophic cardiomyopathy: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(23). doi:10.1161/CIR.0000000000001250. PMID:.
• Wilde AAM, Semsarian C, Márquez MF, Shamloo AS, Ackerman MJ, Ashley EA, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. Europace. 2022;24(8):1307-67. doi:10.1093/europace/euac030. PMID:; PMCID: PMC9435643.