Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review

Abstract

Hereditary cardiomyopathies (CMPs), including arrhythmogenic cardiomyopathy (ACM), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM), represent a group of heart disorders that significantly contribute to cardiovascular morbidity and mortality and are often driven by genetic factors. Recent advances in next-generation sequencing (NGS) technology have enabled the identification of rare variants in both well-established and minor genes associated with CMPs. Nowadays, a set of core genes is included in diagnostic panels for ACM, DCM, and HCM. On the other hand, despite their lesser-known status, variants in the minor genes may contribute to disease mechanisms and influence prognosis. This review evaluates the current evidence supporting the involvement of the minor genes in CMPs, considering their potential pathogenicity and clinical significance. A comprehensive analysis of databases, such as ClinGen, ClinVar, and GeneReviews, along with recent literature and diagnostic guidelines provides a thorough overview of the genetic landscape of minor genes in CMPs and offers guidance in clinical practice, evaluating each case individually based on the clinical referral, and insights for future research. Given the increasing knowledge on these less understood genetic factors, future studies are essential to clearly assess their roles, ultimately leading to improved diagnostic precision and therapeutic strategies in hereditary CMPs.

Keywords: ACM; ARVC; DCM; HCM; cardiomyopathies; genetics.

Figure 1

Representation of genes associated with ACM, DCM, and HCM. The circle sections are color-coded, with orange nuances indicating definitive classification and gray nuances indicating minor (moderate and/or limited) classification. Underlined genes are implicated in more conditions.

Figure 2

Distribution of VUS and P/LP variants in minor genes reported in ClinVar [47] in ACM, DCM, and HCM cases. The bars are color-coded, with red indicating P/LP variants and gray indicating variants of uncertain significance. The background colors represent the ClinGen [45,47] classification for each gene: orange for moderate, yellow for limited, and light gray for not associated.