Clinical care of family members of patients with dilated cardiomyopathy

Abstract

Genetic family screening following the detection of a pathogenic or likely pathogenic variant in a proband with dilated cardiomyopathy (DCM) remains one of the main applications of genetic testing. While cardiac screening is recommended for all first-degree relatives, the a priori risk among family members varies. Consequently, screening regimens should be tailored according to both genetic and clinical information at the individual and familial level. This clinical consensus statement provides tools to help with the risk assessment and follow-up of screening for family members and discusses the utility for integration of genotype-specific information, cardiac imaging, and electrocardiogram findings to personalize cardiac screening regimens, which in conjunction will likely improve individualized risk prediction. Early phenotypic detection of DCM in family members remains an active area of research and innovation. In addition, data are starting to accrue on the utility of early therapeutic intervention in family members with very mild phenotypes that may inform future management in addition to screening. A systematic strategy is proposed to determine the a priori risk of developing DCM for a family member, and the potential of integrating genotype-phenotype knowledge towards family management. Lastly, there is a focus on the current knowledge gaps and ongoing and future opportunities to improve risk prediction, early disease detection, and treatment of family members of patients with DCM.

Keywords: Dilated cardiomyopathy; Family members; Genetics; Screening.

Graphical Abstract

The results of genetic testing of the proband determines the options for a family member (phase 1). When a (likely) pathogenic variant is detected, the family member can choose to test for this variant (phase 2). In the absence of a (likely) pathogenic variant in the family, the risk for the family member to develop dilated cardiomyopathy can increase if multiple family members have the disease (phase 3). The results of phase 1-3 determines the risk for the family member to develop dilated cardiomyopathy, and can help to guide the cardiac follow-up. AI-ECG, artificial intelligence-guided electrocardiography; DCM, dilated cardiomyopathy; GLS, global longitudinal strain.

Figure 1

Characterizing the genetic status of a family with dilated cardiomyopathy. The dashed line at the variant of unknown significance indicates that after cardiac screening and segregation, the variant of unknown significance could be reclassified towards (likely) pathogenic. The dashed line at refrain indicates that family members that refrain from genetic testing for the familial variant should be considered as genotype-positive family members until they are tested for the familial variant. The box with the solid line contains family members with a (mild) phenotype whose follow-up will deviate from unaffected family members, as they will be followed based on their phenotype. The box with the dashed line indicates risk categories of family member without phenotype; see Figure 2 for the follow-up of these individuals. *If the proband has a variant of unknown significance or the genotype is unknown, cardiac screening of the first-degree family members is advised before potential genetic testing. When a (minor) phenotype is detected (Table 1), genetic testing of the affected family member can be considered. **Definition of familial disease: two or more individuals (first- or second-degree family members) in a single family who are diagnosed with dilated cardiomyopathy, or a proband with dilated cardiomyopathy and a first-degree family member with autopsy-proven dilated cardiomyopathy or sudden death below the age of 50 years

Figure 2

Screening and long-term follow-up of family members based on their a priori risk to develop dilated cardiomyopathy. Clinical screening is indicated for every first-degree family member of a patient with dilated cardiomyopathy according to the 2023 European Society of Cardiology guidelines on the management of cardiomyopathies. ^Consider termination of periodic screening at the age of 50 years based on clinical information of the proband (e.g. presence of other non-ischaemic aetiologies of dilated cardiomyopathy and age of diagnosis in proband) in an individual with normal cardiac investigations. †See Table 5 for further details