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Page 34 Loong et al. J Transl Genet Genom 2023;7:27-49 https://dx.doi.org/10.20517/jtgg.2022.20

DCM
DCM is characterized by left ventricular or biventricular dilation and impaired contraction unexplained by
[28]
abnormal loading conditions (e.g., hypertension and valvular heart disease) or ischemic heart disease .
[9]
DCM is a common cause of heart failure and a common indication for cardiac transplantation . There is an
estimated prevalence of 40 cases per 100,000 individuals, with differences between demographic groups
such as race and age of presentation [9,29] . Notably, DCM also accounts for 60% of cardiomyopathies in
childhood [30,31] . The etiology of DCM varies, with contributions commonly from genetic/familial causes and
non-genetic causes. The latter includes familial DCM resulting from sarcomeric gene variants,
neuromuscular disorders (e.g., Duchenne’s muscular dystrophy), inherited mitochondrial disorders, drugs
(e.g., antineoplastic drugs), infections (e.g., infectious myocarditis) and others [9,32] .

Familial DCM is associated with more than 50 genes, many of which encode for sarcomeric proteins and
the well-known LMNA gene [33,34] . Up to 25% of familial DCM bear causal pathogenic variants in the TTN
[32]
gene, whereas LMNA and MYH7 contribute 6% and 4%, respectively . Genetic testing is indicated to
diagnose DCM, and the diagnostic yield for genotype-positive DCM can be as high as 25% [34,35] .
Interestingly, studies reported an overlap of disease-causing variants in a significant proportion of DCM
patients, with 38% of 639 DCM patients having compound or combined variants with HCM and
channelopathy-causing variants . This finding highlights the need for precise phenotyping and additional
[36]
research to understand DCM’s molecular interactions and genotype-phenotype correlations.

Genetic testing also plays some role in outcomes prediction, with some studies demonstrating a higher risk
of ventricular arrhythmias and SCD in those harboring specific variants in LMNA, PLN, RBM20, and
FLNC [37-42] . Another observational study reported that genotype-positive DCM patients had worse outcomes
with increased rates of major adverse cardiovascular events and end-stage heart failure than genotype-
negative patients . Among genotype-positive DCM patients, the clinical course of DCM differs depending
[37]
[37]
on the implicated gene . Additional research is needed for validation and replication.
DCM management focuses on symptomatic treatment and preventing sudden death, including managing
heart failure, its complications, and ICD implantation [27,28] . Currently, targeted therapeutics are being
[43]
studied, with several novel therapeutic approaches, including new myosin activators showing some
promise. In addition to the standard therapies in the guidelines for DCM care, more are needed to advance
[44]
DCM management .
ACM
ACM is a group of familial cell-to-cell junction cardiomyopathies underpinned by cardiac desmosome
abnormalities, resulting in myocyte detachment and alteration of intracellular signal transduction.
[45]
Pathological features include myocyte loss, and fibrofatty replacement of myocardium . ACM predisposes
patients to sustained ventricular arrhythmias, progressive ventricular dysfunction, and a high risk of SCD,
[12]
especially among the young . The literature estimates that the incidence of ACM is anywhere between 1/
1000 and 1/5000 individuals. Guidelines suggest that the diagnosis of ACM requires a high degree of clinical
suspicion with investigations such as imaging (transthoracic echocardiography or cardiac magnetic
resonance imaging [cMRI]), tissue characterization (endomyocardial biopsy), repolarization and
depolarization abnormalities (electrocardiography [ECG]), arrhythmia (Holter ECG monitoring), and
family history .
[46]

Numerous pathogenic variants have been reported for ACM, with approximately half of ACM patients
showing a pathogenic variant in one or more desmosome genes. Pathogenic PKP2 variants are most