Cardiomyopathies comprehensive panel

Hereditary cardiomyopathies are genetic heart muscle diseases characterised by structural and/or functional impairments of the heart muscle. They can lead to heart failure, cardiac arrhythmias, and sudden cardiac death.

The major clinically recognised forms of cardiomyopathy include:

: In HCM, the heart muscle, especially the left ventricle, is thickened (hypertrophied). This thickening can impair heart function and lead to cardiac arrhythmias.

: DCM is characterised by enlargement (dilatation) of the heart chambers and reduced heart muscle contraction, which can lead to heart failure.

: In RCM, the heart muscle becomes stiff and less elastic, which leads to restricted filling of the heart chambers and impairs heart function.

: The right ventricle is primarily affected, and myocardial tissue is replaced by fatty or connective tissue. ACM was therefore previously also referred to as arrhythmogenic right ventricular cardiomyopathy (ARVC). ACM can lead to cardiac arrhythmia and heart failure.

: NCCM is characterised by incomplete compaction of the heart muscle wall. An additional layer of non-compacted trabecular muscle tissue remains, especially in the left ventricle. However, the classification of NCCM remains controversial, as current evidence does not support its recognition as a distinct cardiomyopathy. Instead, several expert groups consider it a morphological phenotype that may occur in various cardiac conditions like DCM.

Estimated prevalences are approximately 1/500 for HCM, 1/2,500 for DCM, 1/1,000 to 1/5,000 for ARVC, and 2-5 % of cardiomyopathies for RCM.  Approximately 30% of nonsyndromic HCM and 27% of DCM cases carry a pathogenic or likely pathogenic germline variant identifiable on current testing.

The genetic conditions associated with cardiomyopathies follow heterogeneous inheritance patterns. Nonsyndromic HCM and DCM are predominantly inherited in an autosomal dominant manner, with autosomal recessive, X-linked (notably DMD-related DCM), and mitochondrial inheritance described for individual entities.

In genetic analysis for cardiomyopathies, all of the above forms are examined in parallel. This can be particularly helpful if the patient does not show a clear clinical picture (e.g., HCM) and genetic analysis can contribute to the diagnosis. Genetic analysis for cardiomyopathies should be considered in the following situations:

• Family history: There are multiple cases of cardiomyopathic diseases in the family.
• Symptoms/abnormal imaging: The patient shows clinical symptoms that can be attributed to cardiomyopathy, or echocardiography/cardiac MRI has revealed evidence of cardiomyopathy. Moreover, recent studies indicate that a relevant proportion of patients with recurrent myocarditis carry pathogenic variants in cardiomyopathy-associated genes (22% in adults; 45% in minors), particularly in cases with complicated or severe disease courses, which underscores the importance of including cardiomyopathy gene testing in these patients.
• Prevention: Genetic analysis may be useful for early diagnosis and prevention of complications in relatives of patients with genetically confirmed cardiomyopathies.

Genetic analysis can help confirm the diagnosis, identify patients at risk, and develop targeted therapeutic measures or preventive strategies.

In patients with suspected inherited cardiomyopathy, molecular genetic testing is an important component of the diagnostic work-up. According to the , genetic testing accompanied by pre- and post-test genetic counselling is recommended as part of the clinical evaluation of patients with cardiomyopathy (Class I). Genetic testing should be interpreted within the broader clinical context, incorporating phenotype, imaging findings, family history, and other diagnostic investigations.

A confirmed molecular diagnosis can establish the underlying aetiology, increase diagnostic certainty, and facilitate differentiation between distinct cardiomyopathy subtypes and their phenocopies. Identification of the causative gene may provide prognostic information, support aetiology-driven management, and, in selected disorders, influence surveillance strategies, arrhythmic risk assessment, and therapeutic decision-making. The clinical relevance of genetic findings varies among cardiomyopathy entities and specific disease genes.

Genetic testing is particularly valuable 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. This allows identification of relatives who require ongoing clinical surveillance while enabling genotype-negative family members to be reassured and, in many cases, discharged from repeated cardiological follow-up.

In disorders with age-dependent penetrance, predictive genetic testing in clinically unaffected children should be performed according to disease-specific recommendations and ideally within an experienced multidisciplinary cardiogenetics framework.

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