Prognostic Prediction of Genotype vs Phenotype in Genetic Cardiomyopathies

Abstract

Background: Diverse genetic backgrounds often lead to phenotypic heterogeneity in cardiomyopathies (CMPs). Previous genotype-phenotype studies have primarily focused on the analysis of a single phenotype, and the diagnostic and prognostic features of the CMP genotype across different phenotypic expressions remain poorly understood.

Objectives: We sought to define differences in outcome prediction when stratifying patients based on phenotype at presentation compared with genotype in a large cohort of patients with CMPs and positive genetic testing.

Methods: Dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy, left-dominant arrhythmogenic cardiomyopathy, and biventricular arrhythmogenic cardiomyopathy were examined in this study. A total of 281 patients (80% DCM) with pathogenic or likely pathogenic variants were included. The primary and secondary outcomes were: 1) all-cause mortality (D)/heart transplant (HT); 2) sudden cardiac death/major ventricular arrhythmias (SCD/MVA); and 3) heart failure-related death (DHF)/HT/left ventricular assist device implantation (LVAD).

Results: Survival analysis revealed that SCD/MVA events occurred more frequently in patients without a DCM phenotype and in carriers of DSP, PKP2, LMNA, and FLNC variants. However, after adjustment for age and sex, genotype-based classification, but not phenotype-based classification, was predictive of SCD/MVA. LMNA showed the worst trends in terms of D/HT and DHF/HT/LVAD.

Conclusions: Genotypes were associated with significant phenotypic heterogeneity in genetic cardiomyopathies. Nevertheless, in our study, genotypic-based classification showed higher precision in predicting the outcome of patients with CMP than phenotype-based classification. These findings add to our current understanding of inherited CMPs and contribute to the risk stratification of patients with positive genetic testing.

Keywords: ALVC; ARVC; DCM; genotype; pathogenic/likely pathogenic variants; phenotype.

FIGURE 1

Gene Variants and Phenotypic Distribution of the Study Population A brief description our final study population elucidating the number of patients enrolled with pathogenic/likely pathogenic variants (P/LP) in the selected genes and their phenotypes at enrollment. (A) Histograms showing the number of patient carriers of P/LP variants in each gene or gene-group of our study population. (B) The same histograms with (C) annexed table, reporting the phenotypic distribution of patient carriers of P/LP variants in each gene or gene-group. ALVC = left dominant arrhythmogenic cardiomyopathy; ARVC = arrhythmogenic right ventricular cardiomyopathy; BiV = biventricular arrhythmogenic right ventricular cardiomyopathy; DCM = dilated cardiomyopathy; DSP = desmoplakin; FLNC = filamin C; LMNA = lamin; PKP2 = plakophilin 2; SARC = sarcomeric genes; TTN = titin.

FIGURE 2

Survival Analysis of the Study Population Based on Genotype Gene-specific survival curves for each outcome, showing LMNA carriers at the highest risk of D/HT and DSP, PKP2, FLNC, and LMNA with higher and comparable sudden cardiac death (SCD)/major ventricular arrhythmia (MVA) risks. (A) (Left) Kaplan-Meier curves for D/HT endpoint. (Right) The same curves split singularly for each gene/gene group. (B) CIF curves for the SCD/MVA endpoint. (Right) The same curves split singularly for each gene/gene group. (C) CIF curves for the DHF/HT/LVAD endpoint. (Right) The same curves split singularly for each gene/gene group. (D) Table reporting the counts of each endpoint for each gene/gene group. D = all-cause mortality; DHF = heart failure-related death; CIF = cumulative incident fraction; HT = heart transplantation; LVAD = left ventricular assist device; other abbreviations as in Figure 1.

FIGURE 3

Survival Analysis of “Arrhythmic Genes” Compared With TTN and SARC Patient carriers of “arrhythmic genes” variants (DSP, FLNC, LMNA, and PKP2), were associated with a significantly higher risk of D/HT (P = 0.031) and SCD/MVA (P < 0.001) compared with carriers of TTN and SARC variants. (A) Kaplan-Meier curves for the primary endpoint (D/HT). (B) CIF curves for the SCD/MVA secondary outcome. (C) CIF curves for the DHF/HT/LVAD outcome. (D) Table reporting the counts of each endpoint. Abbreviations as in Figures 1 and 2.

CENTRAL ILLUSTRATION

Toward Genotype-Based Classification of Nonhypertrophic Cardiomyopathies for Precise Risk Prediction Approximately one-third of patients with nonhypertrophic cardiomyopathies are found to be carriers of monogenic disease-causing variants. If patients are grouped according to phenotype or genotype, a different risk prediction is obtained. PKP2, FLNC, DSP, and LMNA (arrhythmic genes) are associated with a higher risk of D/HT and SCD/MVA with respect to TTN/SARC genes, regardless of phenotypic presentation. ACM = arrhythmogenic cardiomyopathy; ALVC = left dominant arrhythmogenic cardiomyopathy; ARVC = arrhythmogenic right ventricular cardiomyopathy; B = basal evaluation; BiV = biventricular arrhythmogenic right ventricular cardiomyopathy; DCM = dilated cardiomyopathy; D/HT = all-cause mortality/heart transplantation; DSP = desmoplakin; F = follow-up evaluation; FLNC = filamin C; LMNA = lamin; PKP2 = plakophilin 2; P/LP = pathogenic/likely pathogenic SARC = sarcomeric genes; TTN = titin; SCD/MVA = sudden cardiac death/major ventricular arrhythmias.