Genetic Variants in Panamanian Patients with Hereditary Cardiomyopathies

José A. Cedeño-Escudero ^1,2 , Luis A. Sotillo-Bent ^1,2, Evelyn Medina-Batista ¹, Luis A. Méndez-Rosado ^3,*

1. National Specialized Center for Medical Genetics and Genomics of the Ciudad de la Salud, Panama

2. Faculty of Medicine, University of Panama, Panama

3. National Center for Medical Genetics, Havana, Cuba

* Correspondence: Luis A. Méndez-Rosado

Academic Editor: Jaroslav Alois Hubáček

Received: January 26, 2026 | Accepted: May 14, 2026 | Published: May 20, 2026

OBM Genetics 2026, Volume 10, Issue 2, doi:10.21926/obm.genet.2602342

Recommended citation: Cedeño-Escudero JA, Sotillo-Bent LA, Medina-Batista E, Méndez-Rosado LA. Genetic Variants in Panamanian Patients with Hereditary Cardiomyopathies. OBM Genetics 2026; 10(2): 342; doi:10.21926/obm.genet.2602342.

© 2026 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

1. Introduction

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.

2. Materials and Methods

2.1 Study Design and Patient Cohort

This was an observational, descriptive, cross-sectional study. Patients were referred with a clinical diagnosis of hereditary cardiomyopathies or cardiac arrhythmias by the Cardiology Service at the Dr. Arnulfo Arias Madrid Hospital Complex, Ciudad de la Salud, and the Hospital de Especialidades Pediátricas, all belonging to the Caja de Seguro Social (Social Security Fund) of Panama.

2.2 Genetic Analysis

Next-Generation Sequencing (NGS) was performed on these patients between 2019 and 2023 using a targeted panel of 128 genes associated with the most frequent hereditary cardiomyopathies and arrhythmias.

2.3 DNA Extraction and Quality Control

Genomic DNA was extracted and purified from a peripheral blood sample collected in EDTA using the QIAamp^® genomic DNA Kit41. DNA concentration and quality were assessed via spectrophotometry and fluorometry (using the EPOCH and Qubit systems, respectively).

2.4 Sequencing Protocol

The sequencing reaction mixture was prepared using a capture-based technology assay (SOPHiA EXTENDED CARDIO SOLUTION™), followed by Next-Generation Sequencing on the Illumina MiniSeq platform. This process targeted the coding regions and splice sites (±5 base pairs) of the 128 most relevant genes (a total target region of 470 kb) associated with arrhythmias and cardiomyopathies.

2.5 Bioinformatic Analysis

Sequence reads were aligned to the reference human genome [GRC37.12 (HG19)]. Subsequent filtering and variant analysis were conducted using the bioinformatics tools SOPHiA DDM^® (Switzerland), Franklin by Genoox, and Varsome.

2.6 Ethical Considerations

This investigation received approval from the following bodies: the authorities of the Caja de Seguro Social (CSS) of Panama, the General Directorate of Public Health, and the Institutional Research Ethics Committee of the Caja de Seguro Social (DENSYPS-DENADOI-N-404-2024). Access to the database containing the records of patients who underwent sequencing for the diagnosis of hereditary cardiopathies was approved by the Director of the National Specialized Center for Medical Genetics and Genomics of the Ciudad de la Salud, Panamá. Informed consent was waived for this study as the information was collected retrospectively from patient records within the aforementioned database. The privacy and anonymity of all studied patients were rigorously maintained.

3. Results

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.

Table 1 Characterization of the studied patients according to cardiomyopathy type, sex, age at disease onset, and family history.

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).

Table 2 NGS results according to the type of cardiomyopathy studied.

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.

Table 3 Gene variants (LP and P) involved in the studied cardiomyopathies and the specific protein affected.

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.

3.1 Novel Genomic Pathogenic Variants

Four likely pathogenic variants associated with cardiomyopathies that have not been previously reported in the scientific literature were identified (Table 4). The description of these variants follows:

1. Variant 1: FLNC c.6305C>T in a 59-year-old male patient with Hypertrophic Cardiomyopathy [5].
2. Variant 2: TTN c.11806C>T in a 38-year-old female patient diagnosed with Dilated Cardiomyopathy.
3. Variant 3: DSC2 c.354+1G>T in a 66-year-old female patient with Hypertrophic Cardiomyopathy.
4. Variant 4: LAMA4 c.661T>A in a 48-year-old male patient with Dilated Cardiomyopathy.

Table 4 Pathogenic variants found and not previously reported in the literature.

4. Discussion

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.

4.1 Novel De Novo Variants

Genetic factors play a significant role in CM, with pathogenic variants in different genes associated with the regulation of myocardial structure and function. These pathogenic genetic variants affect essential protein domains, explaining the development of these pathologies in patients.

In the case of the FLNC c.6305C>T variant [5], the ROD2 domain was affected; this domain is widely described in the scientific literature to be associated with hypertrophic cardiomyopathy [19,20]. This group of 18-21 nucleotides (within the ROD2 domain) interacts with Z-disc proteins and proteins related to muscle development and contraction. Furthermore, it is of special interest as it constitutes a crucial point in protein phosphorylation [18]. It has been indicated that this ROD2 subdomain is essential for FLNC dimerization and the acquisition of the protein's secondary structure. Therefore, missense variants in the ROD2 subdomain can produce a misfolded protein with deficient cross-linking, provoking a sarcomeric disorder [21,22]. Given that the patient is currently living and their clinical status did not warrant such a high-risk invasive procedure, histopathological studies of the cardiac tissue were not performed. The potential myocardial damage resulting from this mutation was hypothesized based on existing literature [19,20,21,22]. However, Brodehl et al. identified cytoplasmic inclusions indicative of protein aggregates in de novo missense variants of FLNC. Therefore, it cannot be ruled out that a similar pathological process occurred in the clinical case reported herein [23].

The TTN c.11806C>T variant generates a stop codon at position p.(Arg3936*), truncating the Titin protein in the Ig-like domain (specifically, the I-band region of Titin). The structure of Titin is modular, consisting of repeating Immunoglobulin-like and Fibronectin type III (FN3) domains. The I-band (elastic region) contains tandem immunoglobulin domains that act as molecular springs, providing passive rigidity to sarcomeres [24]. This genetic variant at p.Arg3936* leads to premature termination, which likely alters downstream immunoglobulin domains and the structural integrity of the protein. These domains interact with proteins such as obscurin and muscle-specific kinases (e.g., titin kinase), regulating hypertrophic signaling. Truncations in the immunoglobulin domains (especially in the I-band) are strongly associated with DCM due to the loss of structural and signaling functions [25,26,27].

The genetic variant in the DSC2 gene that affects the splicing region will provoke a significant change in the conformation of the Desmocollin-2 protein, a crucial component of desmosomes—structures for cell-cell adhesion important in tissues such as the heart and skin. This probably alters the extracellular cadherin (EC) domains, particularly EC1-EC2, as exon 3 encodes part of the N-terminal extracellular region. Mutations at the splice donor site (such as +1G>T) usually provoke exon skipping or intron retention, altering protein function [28]. This is because mutations within the splice region interfere with the accurate processing of mRNA, leading to mRNA decay and the subsequent loss of desmocollin-2 protein expression. Recently, Brodehl et al. reported a homozygous 4-bp DSC2 deletion resulting from segmental interstitial uniparental isodisomy of chromosome 18, which induced a frameshift in a patient with arrhythmogenic cardiomyopathy (ACM). This frameshift impaired proper mRNA formation and similarly triggered the degradation of the mutant DSC2 mRNA, resulting in the loss of desmocollin-2 variants and ultimately leading to the patient's cardiomyopathy. Consequently, distinct variants of the DSC2 gene may alter the protein through a consistent molecular pathomechanism involving defective mRNA processing [29].

The p.(Cys221Ser) variant of the LAMA4 gene affects the Laminin α4 protein, a key subunit of laminins, which are extracellular matrix glycoproteins essential for the structure and function of basement membranes. According to protein structural data, the Cys221 residue is located within the EGF-like (epidermal growth factor-like) domain (LE), which forms part of the central region of the protein [30]. These EGF-like domains are rich in cysteines and form disulfide bridges, which are crucial for the protein's structural stability. The LE domains in laminins are involved in calcium binding, protein folding, and interactions with other extracellular matrix components. They play a role in cell adhesion, signaling, and tissue integrity, particularly in the heart muscle. Mutations in this domain (such as Cys221Ser) can disrupt disulfide bonds, leading to improper protein folding and cardiomyopathy [31].

Conclusively, family screening remains essential, and relatives would benefit from early detection and intervention to prevent subsequent adverse outcomes. In most developing countries, a unified national system for genetic analysis and family follow-up for hereditary cardiomyopathies is not yet consolidated. This study in Panama aims to serve as a bridge for future collaboration among different medical specialties in the country, benefiting our cardiac patients and their families.

5. Conclusions

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.

Acknowledgments

We wish to express our gratitude to the pediatricians, cardiologists, and pathologists who so kindly collaborated in this investigation.

Author Contributions

José A. Cedeño-Escudero and Luis A. Méndez-Rosado: conceptualized and designed the research study. Reviewed and edited the manuscript. Luis A. Sotillo-Bent: Proper interpretation of results. Reviewed and edited the manuscript. Evelyn Medina-Batista: Methodology, writing – review and editing. Luis A. Méndez-Rosado: Conceptualization, writing – original draft, writing – review and editing. All authors have read and approved the published version of the manuscript.

Competing Interests

The authors have declared that no competing interests exist.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author (M.R.). Furthermore, supplementary files containing the results in a database format were submitted to the journal's editorial office alongside this manuscript.

Additional Materials

The following additional materials are uploaded at the page of this paper.

1. Supplementary files.