Cannie, Douglas Ewan; (2024) Determining the impact of a genetic diagnosis in patients and relatives with dilated cardiomyopathy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background: The clinical impact of genetic testing on dilated cardiomyopathy (DCM) patients and their families has been debated. / Methods: Cohorts of genotyped DCM patients and their relatives were established from the Barts Heart Centre and University College London database and from international collaboration. Baseline, follow-up and outcomes data were collected and managed using a Research Electronic Data Capture (REDCap) database. Analyses were conducted using the Python programming language. Cohorts were stratified by age, sex and genotype for comparisons of yield of genetic testing, disease penetrance and adverse events including a primary composite endpoint of end-stage heart failure and malignant ventricular arrhythmia (MVA). Predictors of adverse events were explored. / Results: 28% of DCM patients returned a likely pathogenic or pathogenic variant from genetic testing. The yield was 23% in patients over 55 years of age. There was no significant difference between genotype positive patients over and under 55 years for the primary composite endpoint (log-rank p = 0.93). Genotype negative patients had the lowest incidence rate of the primary composite endpoint at 1.3 per hundred person years and LMNA variant carriers the highest at 6.0. Rates in TTN variant carriers were similar to those in genotype negative patients and DSP and RBM20 variant carriers were approximately two-fold and three-fold that of the genotype negative group, respectively. Rates of MVA in male EMD variant carriers was similar to that of male LMNA variant carriers. Predictors of adverse events differed by sex and by genotype. The incidence rate of disease penetrance in clinically-unaffected, genotype positive relatives during follow-up was 11.6 per 100 person years. Rates were significantly different between males and females. LMNA variant carriers had the highest incidence rate of disease penetrance at 17.7 per 100 person-years. / Conclusions: DCM phenotype, rates of disease progression and the incidence of adverse events differ significantly by genotype. The yield of genetic testing in older DCM patients is clinically relevant and adverse event rates are comparable to younger genotype positive patients. The impact of a genetic diagnosis in patients and their relatives is substantial.

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