Disease penetrance in genotype-positive relatives from families with dilated cardiomyopathy

• Published in: European heart journal Vol. 44; no. Supplement_2
• Main Authors: Cannie, D, Syrris, P, Protonotarios, A, Bakalakos, A, Lorenzini, M, Guttmann, O, Lopes, L, O'mahony, C, Sekhri, N, Savvatis, K, Mohiddin, S, Elliott, P
• Format: Journal Article
• Language: English
• Published: 09.11.2023
• ISSN: 0195-668X; 1522-9645
• DOI: 10.1093/eurheartj/ehad655.1864

Abstract Background Genetic testing of patients with dilated cardiomyopathy (DCM) results in identification of a causative gene variant in around 19-37% of individuals [1]. Serial clinical assessment of relatives found to carry genetic variants is recommended, but there are no data to guide screening intervals or to better understand the influence of age, sex and genotype on disease expression. Purpose To evaluate the trajectory of disease development in clinically unaffected relatives with a positive genetic test. Methods Families with a likely pathogenic or pathogenic variant in DCM related genes were identified from the database at a cardiomyopathy unit. Families were included only where phenotypes were consistent with DCM or hypokinetic non-dilated cardiomyopathy [2]. Consecutive relatives from these families were retrospectively recruited where they had tested positive for the familial genetic variant and were clinically unaffected at baseline evaluation. Incidence rates of disease penetrance during follow-up were stratified by sex and genotype. Results 131 relatives (59 male (45%) with median age 28.6 [21.5 – 42.0] years at first evaluation) representing 75 families were included. The most prevalent genotypes were DSP (46/131, 35.1%), TTN (32/131, 24.4%) , LMNA (22/131, 16.8%), RBM20 (14/131, 10.7%) and BAG3 (8/131, 6.1%). The overall incident rate of phenotype development during follow-up was 11.6 [8.9 – 14.2] per 100 person years and rates were significantly different between males and females (16.1 versus 8.8 per 100 person-years, log-rank p value = 0.006; Figure 1). LMNA variant-carriers had the highest incidence rate of disease penetrance at 17.7 [9.8 – 25.7] per 100 person-years and disease penetrance occurred at a younger age than DSP and TTN variant-carriers (Figure 2). Conclusions Disease development during follow-up is common in genotype-positive relatives, particularly in males and in LMNA variant-carriers. Genotype-positive relatives should be rescreened at least once each year.Figure 1Figure 2