p.27 抽出テキスト

6.8 Genetic testing and counselling

6.8.1. Genetic architecture Familial forms of cardiomyopathies show diverse modes of inheritance. Gene identification has, over the last three decades, primarily focused on the identification of Mendelian (monogenic) disease genes that most commonly display autosomal dominant inheritance, although other inheritance patterns including autosomal recessive, X-linked, and mitochondrial (matrilineal) are also observed (Table 5). Major genes currently associated with different types of cardiomyopathies are listed in Table 10. Cardiomyopathies are characterized by a marked genetic and allelic heterogeneity, that is, many different variants in many different genes can cause the same phenotype. Rare pathogenic variants associated with cardiomyopathies often exhibit the phenomena of incomplete and age-related penetrance, and variable expressivity.178,179 That is, not all individuals carrying a causative variant manifest the disease and, among those who do, there is broad variability in age of onset and disease severity. Thus, while some individuals may have severe disease necessitating cardiac transplantation at a young age, others may remain unaffected throughout their lives or are only mildly affected. This variability could be due to heterogeneity among causative variants, the additional contribution of non-genetic (clinical, environmental) factors (e.g. hypertension in HCM,180 exercise in ARVC181), and the co-inheritance of additional genetic factors, which act to exacerbate or attenuate the effect of the principal Mendelian genetic variant on the phenotype. This is an active area of research, and recent genome-wide association studies conducted in patients with HCM have provided strong evidence for the modulatory role of common genetic variants of individually small effect that collectively modulate the effects of Mendelian variants (Figure 8).182,183 Across the different cardiomyopathies, the proportion of cases with a confident genetic diagnosis (that is with identification of a likely causal Mendelian genetic variant) is relatively low (e.g. as low as ∼40% in HCM124 and ∼30% in DCM184–186). Genome-wide association studies of common variants in HCM and DCM have provided empirical evidence for substantial polygenic inheritance in these cardiomyopathies.182,183,187 Contrary to Mendelian inheritance, where a single, large-effect variant primarily determines susceptibility to the disorder, complex inheritance rests on the co-inheritance of multiple susceptibility variants. Although not yet studied systematically, besides common variants of small effect, intermediate-effect variants with effect sizes and frequencies between common and Mendelian variants are also expected to contribute to such complex inheritance.188 It is likely that cardiomyopathies span a continuum of genetic complexity, with Mendelian forms at one end, determined primarily by the inheritance of an ultrarare large-effect genetic variant, and highly polygenic forms at the other (see Figure 8). Variants that contribute to disease susceptibility in the setting of complex inheritance likely overlap with those that modulate disease penetrance and expressivity in the Mendelian form of the disease.182,183

6.8.2 Genetic testing

Genetic testing of Mendelian cardiomyopathy genes has become a standard aspect of clinical management in affected families.3 First-line testing should be focused on genes robustly associated with the presenting phenotype. If initial testing does not reveal a cause, but suspicion of a monogenic cause remains high, then more extended sequencing or analysis may be indicated, depending on the family structure and other factors. Once a genetic cause is established in one family member, then other family members may undergo testing for only the causative variant.

Genetic testing in an individual with cardiomyopathy (known as confirmatory testing or diagnostic testing) is recommended for their direct benefit: (i) to confirm the diagnosis; (ii) where it may inform prognosis; (iii) where it may inform treatment selection; or (iv) where it may inform their reproductive management. Genetic testing of an affected individual may be indicated, even if it is unlikely to alter their management, if there are relatives who may benefit from testing, particularly if there are relatives who will be enrolled in longitudinal surveillance if the genetic aetiology is not established and who may be spared this burden if a genetic diagnosis is made in the family (Table 11). Testing may also be helpful in broader contexts, even when not obviously informative for immediate management; for example, a genetic diagnosis may provide psychological benefit in a patient struggling to understand their disease. Genetic testing in a clinically unaffected relative of an individual with cardiomyopathy may be indicated irrespective of age, even in very young children, if a genetic diagnosis has been established with confidence in the affected individual (known as cascade testing, predictive testing, or pre-symptomatic testing). Once a pathogenic/likely pathogenic (P/LP) variant has been identified within an index patient following investigations of relevant disease genes associated with the specific phenotype, it is possible to offer cascade genetic testing of first-degree at-risk relatives, including pre-test genetic counselling (see Section 6.8.3). In a scenario where a first-degree relative has died, evaluation of close relatives of the deceased individual (i.e. second-degree relatives of the index patient) should also be considered. Individuals who are found not to harbour the familial variant can usually be discharged from clinical follow-up; those who do carry the familial variant are recommended to undergo clinical evaluation and usually ongoing surveillance. Cascade testing is not indicated when a variant of uncertain significance is identified in the proband. Sequencing may also be indicated for segregation analysis (rather than as a diagnostic test) to inform interpretation of a variant of uncertain significance found in an affected individual. This is usually limited to individuals who are clearly affected, or to testing of the parents to identify a de novo variant. Genetic counselling in this circumstance would involve clear communication to family members that this is not a diagnostic test, but rather is contributing to clarifying the pathogenicity of the uncertain variant. Finally, the evaluation of cardiac genes for secondary findings where data are generated in the setting of genetic testing for another clinical indication (also referred to as opportunistic screening) may be reasonable where the balance of benefits and harm is known, and if the cost is acceptable. Broader population screening might also prove reasonable if the balance of benefits and harm proves favourable. At present there is insufficient data to evaluate the balance of benefits and harm in either context, and this should currently only be performed in a research context in order to obtain such data. Careful genetic counselling to fully explain benefits and risks in this setting is critical. At present, there are very little data to evaluate this balance and this is an important evidence gap. In the United States of America, the American College of Medical Genetics and Genomics has recommended that cardiomyopathy-associated genes be evaluated for secondary findings whenever broad clinical sequencing is undertaken, regardless of the initial indication for testing.192,193 There is currently no international consensus around this recommendation.

ESC Guidelines                                                                                                                                                                                          3529

Downloaded from academic.oup.com/eurheartj/article/44/37/3503/7246608 by guest on 07 October 2026