Considering complexity in the genetic evaluation of dilated cardiomyopathy

Abstract

Dilated cardiomyopathy (DCM) is a cardiovascular disease of genetic aetiology that causes substantial morbidity and mortality, and presents considerable opportunity for disease mitigation and prevention in those at risk. Foundational to the process of caring for patients diagnosed with DCM is a clinical genetic evaluation, which always begins with a comprehensive family history and clinical evaluation. Genetic testing of the proband, the first patient identified in a family with DCM, within the context of genetic counselling is always indicated, regardless of whether the DCM is familial or non-familial. Clinical screening of at-risk family members is also indicated, as is cascade genetic testing for actionable variants found at genetic testing in the proband. Clinicians now have expansive panels with many genes available for DCM genetic testing, and the approaches used to evaluate rare variants to decide which are disease-causing continues to rapidly evolve. Despite these recent advances, only a minority of cases yield actionable variants, even in familial DCM where a genetic aetiology is highly likely. This underscores that our knowledge of DCM clinical genetics remains incomplete, including variant interpretation and DCM genetic architecture. Emerging data suggest that the single-variant Mendelian disease model is insufficient to explain some DCM cases, and rather that multiple variants, both common and rare, and at times key environmental factors, interact to cause DCM. A simple model illustrating the intersection of DCM genetic architecture with environmental impact is provided.

Keywords: genetics; idiopathic dilated cardiomyopathy.

Figure 1.. The Genetic Evaluation of DCM.

The genetic evaluation of DCM begins with identification of the proband and initiating the guideline-based^, family-based process of comprehensive phenotypic evaluation, family history assessment, genetic counseling, and genetic testing process. Surveillance and management of family members is largely dependent on the genetic testing outcome and risk assessment of the proband. For those who are phenotype positive, medical and device therapy should proceed according to guidelines.

Figure 2.. Genes with evidence supporting an association with DCM.

Genes in which variants have been published in humans with DCM arranged by gene ontology. Genes with the most substantial evidence in their disease association with DCM are noted in bold text. Those with loss of function as an established DCM-causing mechanism are noted with an asterisk (*).

Figure 3.. Definitions and clinical implications of DCM genetic results.

a) First-degree relatives (FDRs) with negative cascade genetic testing (GT) only discharged from follow up in the setting of normal clinical screening and no other indications for cardiovascular follow up. b) If VUS(s) are observed along with a P/LP variant are suspected to further modify the disease, clinical judgment should be carefully exercised when determining if family members should be discharged from screening. Expert CV genetics centers are best to manage the risk assessment and make care recommendations in the setting of unsolved complexity in these cases. c) Cardiologists, genetic counselors, and/or geneticists with expertise in cardiovascular genetics. d) In trying to resolve VUSs, expert evaluation of the pedigree to identify other informative affected family members where testing could inform if a variant is segregating with disease in the family may aid in classification resolution. (B, benign, LB, likely benign).

Figure 4.. Simplified models of gene-environment interactions causing DCM.

Each colored bar represents genetic and environmental factors in individuals with DCM. The height of each bar represents its phenotypic impact to cause DCM. Blue bars represent the genetic contribution of one or more variants in DCM genes to the phenotype. Orange bars represent the environmental contributions to the phenotype. The upper horizontal line shows a threshold for clinically detectable DCM, and when blue, orange, or a combination of both, cross the line, DCM, can be clinically detected. Box A shows classic autosomal dominant DCM, occurring due to a single, highly penetrant, pathogenic variant, whereas Box B shows an individual who developed DCM only from environmental cause. In Box C, neither individual C1 nor individual C2 develop DCM from chemotherapy (CTX) or a moderate impact genetic variant (a), respectively. However, individual C3 develops DCM from two moderate impact variants (a, b), and individual C4 develops DCM when CTX is combined with a moderate impact variant (a). Box D represents cases of near-DCM, not reaching the DCM threshold from genetic, environmental, or gene and environment interaction (D1, D2, D3, respectively). With an added genetic predisposition due to common variants (yellow box), the same single variant, environmental impact, or both (D4, D5, D6, respectively) now reach the DCM threshold. Environmental impacts other than CTX may also facilitate DCM, e.g., excess alcohol ingestion, hypertension.