A combinatorial oligogenic basis for the phenotypic plasticity between late-onset dilated and arrhythmogenic cardiomyopathy in a single family

Abstract

Introduction: Primary dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) are the two common and distinct forms of hereditary cardiomyopathies caused by defined pathogenic variants (PVs) typically in different sets of genes. DCM is characterized by left ventricular dilatation, dysfunction, and failure, whereas ARVC classically involves the right ventricle and is characterized by fibrofatty infiltration of the myocardium. DCM is caused primarily by the PVs in genes encoding sarcomere and cytoskeletal protein, while ARVC is mainly a disease of the desmosome proteins. DCM and ARVC exhibit partial phenotypic and genetic overlaps.

Aim: To analyze the genetic basis of the phenotypic heterogeneity of cardiomyopathy in members of a single family.

Methods and results: We recruited, clinically characterized, and performed whole-exome sequencing in five affected, three probably affected, and two clinically unaffected members of a single family. The family members mainly exhibited late-onset DCM associated with conduction defects and arrhythmias. One family member who died suddenly was diagnosed with the classic ARVC at autopsy and another presented with isolated ventricular tachycardia. A novel splicing (truncating) and a rare missense variant in the TTN gene, likely in cis, co-segregated with the phenotype in all affected and probably affected family members and were likely the causal variants. Several PVs and LPVs in other genes involved in cardiomyopathies and arrhythmias were also identified that seem to modify the expression of the phenotype. Notably, LPVs in the DSP and PKP2 genes, which are known genes for ARVC, were identified in the family member who also carried the TTN variants but developed the classic ARVC.

Conclusion: The findings indicate the causal role of the TTN variants, exhibiting an age-dependent penetrance in late-onset DCM, and highlight the potential modifying role of the concomitant LPVs in additional genes on the expression of the phenotype, including a phenotypic switch from the anticipated DCM to ARVC. The findings support an oligogenic basis of the cardiac phenotype in hereditary cardiomyopathies. A comprehensive genetic analysis involving all PVs and LPVs along with detailed phenotypic characterization is necessary to gain insights into the molecular pathogenesis of hereditary cardiomyopathies.

Keywords: Titin; arrhythmogenic right ventricular cardiomyopathy; desmoplakin; dilated cardiomyopathy; genetic; mutation; pathogenic variant; plakophilin 2; sudden death.

Figure 1.

Pedigree and list of the likely pathogenic variants (LPVs) in genes known to cause cardiomyopathies. Generation and family member identifiers are listed, the latter under each symbol. Gene name and the amino acid change or splice variants are listed under each symbol, indicating presence of the variants in that exome. Square: male; Circle: female; Full circle and square: affected individuals; Open circle and square: unaffected individuals; slash through: deceased individuals. Circle and square with a dot at the center indicate carrier individuals or obligate carrier (II-1). Gray circle with white center identifies an individual with ARVC.

Figure 2.

A 12-lead electrocardiogram in the proband (the upper three panels) and a rhythm strip (lower three panels). The electrocardiogram shows a normal sinus rhythm, probable left atrial enlargement, a normal PR interval, and an increased QRS duration with a normal axis and morphology, indicative of left bundle branch block.

Figure 3.

Echocardiogram and cardiac magnetic image resonance in the proband. Panels A and B show parasternal long axis view of the ventricles in diastole (panel A) and systole (Panel B). The left ventricular end diastolic and systolic diameters were measured 5.64 and 4.47 cm, respectively, and a calculated left ventricular fractional shortening of 21%. Panel C shows myocardial tissue Doppler velocities depicting low velocities. Panel D shows cross sectional myocardial images obtained by magnetic resonance imaging, which shows enlarged ventricles and absence of fibrofatty infiltration of the myocardium.

Figure 4.

Histological findings in a family member with the classic ARVC. Masson trichrome stained myocardial sections, low (upper panel) and high magnification (lower panel) fields, from the right and left ventricles of family member III-4 who died suddenly. Sections from the right ventricle showing infiltration of the right ventricular wall with fibro-adipocytes, whereas the section from the left ventricle shows mild fibrosis.