Hereditary Cardiomyopathies (HCs) are cardiovascular diseases of genetic etiology that may present with a familial pattern. These conditions include cardiomyopathies (CMs), arrhythmias (ARs), diseases of aortic dilation, and other hereditary syndromes affecting the cardiovascular system. Although HCs exhibit high clinical variability, they share a common characteristic: an association with sudden cardiac death, which, in some cases, may be the first or only clinical manifestation [1].

Insights into the genetic causes of cardiomyopathies have greatly advanced our understanding of the molecular basis and pathophysiology of hypertrophic, dilated, arrhythmogenic, restrictive, and left ventricular non-compaction cardiomyopathies. More than a thousand mutations in approximately 100 genes—encoding proteins involved in various subcellular systems—have been identified, underscoring the diversity of pathways that contribute to pathological cardiac remodeling [2].

The psychological burden and impact on the quality of life resulting from a hereditary cardiomyopathy diagnosis are significant for both the patient and their family. This is compounded by the economic impact of these chronic and debilitating diseases, necessitating greater resource utilization for diagnosis and pharmacological management. Many of these patients die without an apparent cause of illness—for instance, while engaging in sports—and a post-mortem examination often yields no explanation for the sudden demise. This uncertainty is devastating for the family.

The European Association for Molecular Pathology recommends conducting toxicological, microbiological, biochemical, and molecular DNA investigations in cases of sudden death of unknown etiology. Furthermore, Basso and colleagues advocate establishing multidisciplinary teams comprising cardiologists, geneticists, and pathologists to ensure accurate identification of the cause of death and to implement appropriate preventive strategies for family members [3].

In Panama, the national incidence of the aforementioned types of hereditary heart diseases is unknown, suggesting an apparent under-registration of these cases. This situation mirrors the international context, where not all countries have established effective strategies and guidelines for the accurate phenotypic and molecular-genetic identification of these conditions [4]. Consequently, this makes it impossible to identify carrier families, estimate the recurrence risk, and implement preventative measures in affected individuals.

The objective of this study is to identify genetic variants in patients diagnosed with Hereditary Cardiomyopathies, establish subsequent identification of carrier families, and provide genetic counseling.

A total of 91 patients presenting with CM, AR, or both were studied, with a predominance of male participants and the CM phenotype. Table 1 Regarding patient status, 40.7% (n = 37) were hospitalized, while 59.3% (n = 54) were treated as outpatients. At the conclusion of this study, no mortality was reported within the cohort. The sample was predominantly urban, with the majority of patients (65.6%) born in the Province of Panama. Ethnicity was not addressed in this study, as defining specific ethnic groups is challenging in Panama due to the high degree of genetic admixture in the population.

In a limited subgroup (n = 17, primarily under 40 years of age), Body Mass Index (BMI) was recorded, ranging from 24.1 to 26 kg/m². However, due to the small sample size for this specific metric, BMI was not included as a formal variable in the final analysis.

Among the 91 patients studied, 102 clinical diagnoses of hereditary cardiomyopathy (HC) were identified. Following the American College of Medical Genetics and Genomics (ACMG) criteria, identified variants were classified as Pathogenic (P), Likely Pathogenic (LP), Variants of Uncertain Significance (VUS), or Negative.

Among the 104 clinical diagnoses, 81 (77.9%) corresponded to CM—with two patients having dual diagnoses—while 23 (22.1%) were identified as AR (Table 2).

The diagnostic yield found for CM was 21% (17/81), and for AR, it was 26.1% (6/23).

Table 2 presents the distribution of patients across the studied conditions, alongside the classification of variants as P, LP, or VUS. It also indicates whether a family history of the disease was present. For improved clarity, the table is categorized into the two primary study cohorts: CM and AR.

Classification of Genetic Variants by Cardiomyopathy Type:

Of the 104 HC diagnoses, P or LP variants were identified in 23% of cases (24/104), while VUS were found in 43.3% (45/104); the remaining 34.6% (36/104) yielded negative results. As this represents a pioneering study in Panama, these findings will serve as the basis for future cascade screening of family members in cases where P or LP variants were identified.

In Table 3, we present the genes detected with P or LP variants, grouped by the type of cardiomyopathy for which they were referred to our institution. A total of 24 P and LP variants were found across 13 different genes.

We highlight the detection of four pathogenic variants in the TTR gene in patients admitted with hypertrophic cardiomyopathy and dilated cardiomyopathy. This gene is fundamentally involved in amyloidosis, a condition characterized by the deposition of insoluble protein fibrils within the extracellular matrix, which may present as cardiomyopathy, among other symptoms. The MYH7 gene presented the highest number of P and LP variants in patients with this CM, accounting for 23% (3/13). The highest number of P and LP variants was detected in patients with Hypertrophic Cardiomyopathy, representing 54% (13/24) of the total.

The pathogenesis of cardiomyopathies is not yet exhaustively understood, and diagnosis constitutes a challenge, partly due to clinical and genetic heterogeneity. Phenomena such as variable expressivity and reduced penetrance occasionally make it difficult to define the heritability of the pathology in certain families.

In the present investigation, 91 patients with a confirmed clinical diagnosis of cardiomyopathy (CM or AR) were analyzed, with both conditions present in 11 patients. Patients with structural cardiomyopathies may occasionally present initially with cardiac conduction disturbances, including ventricular arrhythmias, supraventricular arrhythmias, atrial fibrillation, bradycardia, or atrioventricular blocks [6,7].

Male sex predominated in the cohort; the average age of patients with CM was 46 years, and 41 years for those with AR. Similar characteristics were reported by Martinez et al. [8] and Rucinski et al. [9]. Fifty-three percent of the studied patients had a family history of the disease, which is common as these conditions most often exhibit an autosomal dominant inheritance pattern [8,9].

The majority of patients were from urban areas, likely due to superior access to specialized cardiology consultations and genetic testing facilities. Self-reported ethnicity was excluded from this study; in Latin America, defining distinct ethnic groups is complex due to extensive genetic admixture resulting from Spanish colonization and the subsequent blending of Indigenous, Caucasian, and African populations—A phenomenon well-documented in numerous genomic studies [10,11].

The genealogical tree is one of the most powerful tools in genetics. It is a key step in the anamnesis, which is given significant time during the clinical geneticist's consultation. Family history serves as a diagnostic tool, helping answer key questions such as the pattern of inheritance, whether a molecular study should be requested—and which one—and identifying at-risk relatives.

We identified 23/91 (25.3%) patients with 24 P or LP variants. Knowing the pathogenic variant(s) in the index case enables identification of asymptomatic carriers within the family, facilitating genetic counseling and preventive measures in the management of these cardiomyopathies. Furthermore, this offers reassurance to non-carriers, enabling the conclusion of their clinical monitoring [12,13].

Patients with a family history constituted 57.1% (52/91) of the sample. Within this subgroup, 30.7% (16/52) presented a positive genetic variant (P or LP), 46.1% (24/52) had a VUS, and 23.1% (12/52) were negative. Conversely, the existence of de novo variants must always be considered [14,15]. Currently, guidelines vary among societies regarding the request for genetic testing, particularly for pathologies that may be multifactorial, such as hypertrophic or dilated cardiomyopathy. Our findings support the notion that patients with a family history are more likely to present with a variant classified as Type 4 (LP) or Type 5 (P) according to ACMG/AMP criteria [16,17,18]. However, this does not exclude probands without a positive family history, as these diseases, as mentioned, present with reduced penetrance and variable expressivity.

The identification of Type 4 (LP) and Type 5 (P) genetic variants associated with HCs in the Panamanian population has facilitated appropriate genetic counseling for affected families and enabled the active screening and identification of asymptomatic carriers within these high-risk lineages, which is essential for early intervention and prevention strategies.