Disease Penetrance in Genotype-Positive But Clinically Unaffected Relatives From Families With Dilated Cardiomyopathy.

BACKGROUND

Serial clinical assessment of genotype-positive relatives from families with dilated cardiomyopathy (DCM) is recommended, but there are limited data to guide screening intervals.

OBJECTIVES

This study sought to understand the influence of age, sex, and genotype on disease expression.

METHODS

Families with a DCM phenotype and a likely pathogenic or pathogenic variant in DCM-related genes were identified. Consecutive genotype-positive relatives who were clinically unaffected at baseline assessment were retrospectively recruited. The incidence rates of disease penetrance during follow-up observation were stratified by age, sex, and genotype. A primary composite endpoint of heart failure and malignant ventricular arrhythmia was evaluated.

RESULTS

A total of 130 relatives (59 male [45%], median age: 31.4 years [Q1-Q3: 25.1-47.6 years]) from 74 families were included. The incidence rate of phenotype development during 80 months of follow-up was 11.6 per 100 person-years (Q1-Q3: 9.0-14.3 per 100 person-years). A phenotype developed in more men than women (16.1 vs 8.9 per 100 person-years, respectively; log-rank P value = 0.007). LMNA variant carriers had the highest incidence rate of disease penetrance at 17.7 per 100 person-years (Q1-Q3: 9.8-25.7 per 100 person-years). Baseline LVEF was strongly associated with disease penetrance. Four relatives (3.1%) had the primary composite endpoint; 3 (9.4%) relatives with an implantable cardiac defibrillator received an appropriate shock.

CONCLUSIONS

Rates of disease penetrance are high in genotype-positive relatives and particularly high in men and LMNA variant carriers. Baseline LVEF is strongly associated with disease penetrance. These findings emphasize the importance of regular evaluation of this cohort and underline the potential for tailored screening intervals.