European Journal of Cardiovascular Medicine

Inherited cardiomyopathies represent a group of genetically heterogeneous myocardial diseases that affect the mechanical and electrical functions of the heart. These disorders include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic cardiomyopathy (ACM), and restrictive cardiomyopathy (RCM), among others. They are a major cause of heart failure, arrhythmias, and sudden cardiac death, especially in young individuals and athletes [1]. With the increasing understanding of the genetic basis of these diseases, genetic testing has emerged as a powerful tool for early diagnosis, familial risk assessment, and personalized management.

Hypertrophic cardiomyopathy, one of the most prevalent inherited cardiac disorders, is primarily caused by mutations in sarcomeric protein genes such as MYH7 and MYBPC3 [2]. DCM, although often idiopathic, has been increasingly associated with genetic causes, including mutations in genes encoding cytoskeletal and nuclear envelope proteins like TTN and LMNA [3]. Similarly, ACM is linked to pathogenic variants in desmosomal genes such as PKP2 and DSP [4]. These genetic insights have transformed the clinical approach from phenotype-based diagnosis to genotype-informed precision medicine.

The advent of next-generation sequencing (NGS) has revolutionized the field of cardiovascular genetics by enabling rapid, cost-effective, and simultaneous screening of multiple genes associated with cardiomyopathies [5]. Compared to traditional Sanger sequencing, NGS-based panels have significantly increased the diagnostic yield, especially in conditions like HCM and ACM, where the mutation detection rate can be as high as 60% [6].

Genetic testing offers several advantages in clinical practice. Firstly, it helps confirm the diagnosis in individuals with ambiguous or overlapping phenotypes. Secondly, it facilitates cascade screening of at-risk relatives, enabling early detection and intervention even before the onset of symptoms [7]. Thirdly, genetic data can influence clinical decisions such as the need for implantable cardioverter-defibrillator (ICD) implantation, restriction from competitive sports, or closer surveillance in individuals carrying high-risk mutations [8].

However, the interpretation and clinical application of genetic results come with significant challenges. Variants of uncertain significance (VUS) remain a major limitation, often leaving clinicians and patients in a state of uncertainty. Moreover, the presence of incomplete penetrance and variable expressivity complicates genotype-phenotype correlations. For instance, some individuals harboring pathogenic mutations may remain asymptomatic throughout life, while others may develop severe disease at a young age [9].

Ethical, legal, and psychosocial implications also need to be considered. Genetic counseling is essential before and after testing to ensure informed decision-making and to address issues such as genetic discrimination, anxiety, and reproductive choices. Moreover, disparities in access to genetic testing and counseling services, especially in low-resource settings, remain an important public health concern [10].

In conclusion, genetic testing has become an indispensable component of the evaluation and management of inherited cardiomyopathies. It enables early diagnosis, targeted family screening, and individualized therapeutic strategies. Nevertheless, the optimal integration of genetic testing into routine cardiology practice requires a multidisciplinary approach involving cardiologists, geneticists, and counselors. Ongoing research into novel genes, better interpretation tools, and long-term clinical outcomes will further enhance the utility and accuracy of genetic testing in this domain.

Study design: Narrative review study.

Duration of the Study: 1 Year

Sample Size: 100 Patients

Inclusion Criteria:

• Studies published between 2015 and 2025.
• Peer-reviewed original research articles, reviews, guidelines, and meta-analyses.
• Studies focusing on genetic testing in inherited cardiomyopathies (e.g., HCM, DCM, ACM, RCM).
• Articles discussing next-generation sequencing (NGS) and other modern molecular diagnostic techniques.
• Studies addressing clinical utility, diagnostic yield, genotype-phenotype correlation, and cascade screening.
• Publications in English language.
• Studies involving human subjects (adults or children).

Exclusion Criteria:

• Studies published before 2015.
• Animal studies or basic science research not involving clinical application.
• Articles not addressing genetic aspects of cardiomyopathies.
• Non-English language publications.
• Case reports, editorials, letters to the editor, and conference abstracts without full data.
• Studies focusing on acquired cardiomyopathies (e.g., ischemic, alcoholic, or viral myocarditis).
• Studies with insufficient or inaccessible full-text content.

Statistical Analysis: As this is a narrative review, no original statistical analysis was conducted on primary data. However, statistical outcomes reported in the included studies were analyzed and synthesized to evaluate the diagnostic yield and clinical utility of genetic testing across various inherited cardiomyopathies. Proportions and percentages were reviewed to compare mutation detection rates, with hypertrophic cardiomyopathy (HCM) showing the highest diagnostic yield (up to 60%), followed by arrhythmogenic cardiomyopathy (30–50%) and dilated cardiomyopathy (20–40%). Risk ratios and hazard ratios, where available, were examined to understand genotype-phenotype correlations and the impact of specific mutations on clinical outcomes such as sudden cardiac death, disease progression, and need for device implantation. Variants of uncertain significance (VUS) were noted to comprise 20–30% of identified variants in some cohorts, highlighting limitations in interpretability..

Table 1: Baseline Demographic and Clinical Characteristics (n=100)

Table 2: Distribution of Inherited Cardiomyopathy Subtypes

Table 3: Genetic Testing Yield Based on Family History

Table 4: Most Frequently Detected Pathogenic Variants

Table 5: Clinical Outcome Comparison Based on Mutation Status

Figure 1: Most Frequently Detected Pathogenic Variants

Figure 2: Clinical Outcome Comparison Based on Mutation Status

In our study cohort of 100 patients with inherited cardiomyopathies, the mean age was 42.6 ± 14.3 years, reflecting a wide age range across early adulthood to mid-life. The gender distribution showed a slight male predominance with a male-to-female ratio of 58:42. A positive family history of cardiomyopathy was present in 37% of the patients, suggesting a significant genetic predisposition. Furthermore, 12% of the cohort reported a history of sudden cardiac death (SCD) in first-degree relatives, highlighting the potentially lethal nature of these conditions. Functionally, more than half of the patients (54%) were classified as NYHA Class II or higher, indicating symptomatic heart failure in a substantial portion of the study population. The mean left ventricular ejection fraction (LVEF) was 48.2 ± 8.5%, suggestive of moderately reduced systolic function on average, consistent with the progressive myocardial dysfunction characteristic of cardiomyopathies.

Among the 100 patients evaluated, hypertrophic cardiomyopathy (HCM) was the most frequently observed subtype, accounting for 40% of the cohort. Of these, 70% (n=28) had identifiable genetic mutations, which was statistically significant (p = 0.002), indicating a strong association between HCM and genetic etiology. Dilated cardiomyopathy (DCM) was seen in 35 patients, with 17 (48.6%) showing genetic mutations. Arrhythmogenic cardiomyopathy (ACM) was present in 15 patients, of whom 9 (60%) had identifiable mutations. Restrictive cardiomyopathy (RCM), the least common subtype in this study, was found in 10 patients, with only 3 (30%) demonstrating genetic abnormalities. While HCM showed a statistically significant correlation with identifiable genetic mutations, the other subtypes did not reach statistical significance, possibly due to smaller sample sizes or variable genetic penetrance.

A significant association was observed between positive family history and the presence of genetic mutations in patients with inherited cardiomyopathies. Among the 37 patients with a documented family history, 81.1% (n=30) had a detectable genetic mutation, while only 18.9% (n=7) did not. In contrast, among the 63 patients without a family history, just 42.9% (n=27) showed detectable mutations, and 57.1% (n=36) did not. This difference was statistically significant (p = 0.001), reinforcing the strong correlation between family history and the likelihood of identifying a genetic basis for cardiomyopathy.

In the genetic analysis of patients with inherited cardiomyopathies, several key pathogenic variants were identified, with distribution varying by cardiomyopathy subtype. The MYH7 gene mutation was the most prevalent, detected in 18% of patients, all of whom were diagnosed with hypertrophic cardiomyopathy (HCM). Similarly, MYBPC3 mutations, also associated with HCM, were found in 11% of cases. Among patients with dilated cardiomyopathy (DCM), the most frequently mutated gene was TTN, observed in 14% of the cohort, reflecting its well-established role in DCM pathogenesis. PKP2 mutations, linked to arrhythmogenic cardiomyopathy (ACM), were detected in 6% of patients. Additionally, LMNA gene mutations, known for their association with both DCM and conduction system disease, were found in 5% of cases.

At the 12-month follow-up, clinical outcomes were compared between mutation-positive and mutation-negative patients. Sudden cardiac death (SCD) occurred in 4 patients (7.0%) with identified mutations and 1 patient (2.3%) without mutations; however, this difference was not statistically significant (p = 0.19). Implantation of an implantable cardioverter-defibrillator (ICD) was significantly more frequent in the mutation-positive group (21.1% vs. 9.3%, p = 0.045), suggesting a higher perceived or actual risk of arrhythmic events in these individuals. Heart failure–related hospitalizations were comparable between the groups (15.8% in mutation-positive vs. 11.6% in mutation-negative, p = 0.56), indicating no significant difference in short-term heart failure progression.

In our study, the demographic and clinical profile of patients with inherited cardiomyopathies revealed a strong genetic basis for disease expression, particularly among those with hypertrophic cardiomyopathy (HCM) and a positive family history. The high rate of detectable mutations in HCM (70%) aligns with findings by Alfares et al. (2015), who reported that pathogenic variants in MYH7 and MYBPC3 are the most commonly implicated in HCM, accounting for up to 60–70% of familial cases [11]. Similarly, Walsh et al. (2017) demonstrated that among patients with HCM, sarcomeric gene mutations were detected in 57% of cases, supporting the critical role of genetic screening in diagnosis and risk stratification [12]. The observed mutation rate in dilated cardiomyopathy (DCM) in our study (48.6%) is consistent with the work of Hershberger et al. (2018), who found a mutation detection yield of approximately 40–50%, with TTN truncating variants being the most prevalent [13]. The strong association between a positive family history and genetic mutation detection in our cohort (81.1% vs. 42.9%, p = 0.001) is corroborated by the work of Pugh et al. (2014), who emphasized that the presence of a family history significantly increases the likelihood of identifying a pathogenic variant [14]. Our genetic spectrum also closely mirrors other population-based registries. For instance, Norton et al. (2020) identified PKP2 as the predominant gene in arrhythmogenic cardiomyopathy (ACM), consistent with our findings of a 6% prevalence [15]. Likewise, LMNA mutations, seen in 5% of our cohort, are well-documented in literature as contributors to both DCM and conduction defects, as highlighted by van Rijsingen et al. (2016), who also reported increased arrhythmic risk in LMNA-positive individuals [16]. At 12-month follow-up, although sudden cardiac death (SCD) was not significantly higher in mutation-positive patients (7.0% vs. 2.3%, p = 0.19), ICD implantation was notably more frequent (21.1% vs. 9.3%, p = 0.045), reflecting heightened clinical concern in genetically predisposed individuals. This aligns with the multicenter study by Ingles et al. (2019), which showed that genetic mutation carriers, particularly those with sarcomeric or desmosomal mutations, are more likely to receive ICDs for primary prevention [17]. Our outcome data also resonate with the findings of Mazzarotto et al. (2020), who demonstrated that genotype-positive patients often receive more aggressive surveillance and therapeutic interventions, even in the absence of overt clinical progression [18]. Regarding hospitalization for heart failure, the comparable rates between groups (15.8% vs. 11.6%, p = 0.56) are in line with a recent study by Shah et al. (2021), which suggested that short-term clinical outcomes may not differ significantly between mutation-positive and -negative patients, especially in the early phases of disease [19]. However, long-term prospective data, such as those from the MYOCARDIAL trial (2023), indicate that mutation-positive individuals may demonstrate greater functional decline over time, emphasizing the importance of ongoing monitoring [20].

This study underscores the significant role of genetic testing in the evaluation and management of inherited cardiomyopathies. A high proportion of patients, particularly those with hypertrophic cardiomyopathy and a positive family history, were found to carry pathogenic mutations, with MYH7, MYBPC3, and TTN being the most commonly implicated genes. The strong association between family history and mutation positivity emphasizes the value of detailed pedigree analysis. While clinical outcomes such as sudden cardiac death and heart failure hospitalization were not significantly different between mutation-positive and mutation-negative groups over the short term, the higher rate of ICD implantation among mutation-positive patients.

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