Syndromic dilated cardiomyopathy suggestive of an oligogenic background with CD36 and TNXB variants: a case report

Abstract

Background

Dilated cardiomyopathy (DCM) is a major cause of heart failure and sudden cardiac death and has traditionally been regarded as a predominantly monogenic disorder. However, advances in next-generation sequencing have revealed a more complex genetic architecture with increasing recognition of oligogenic and polygenic contributions; particularly in patients presenting with extracardiac manifestations. In such cases, careful phenotypic characterization and integrative interpretation of genetic findings are essential for accurate diagnosis and management.

Case summary

We report the case of a 46-year-old man who presented with progressive exertional dyspnoea (the New York Heart Association class II–III). His medical history was notable for childhood-onset epilepsy, visual impairment, musculoskeletal abnormalities, and infertility. Transthoracic echocardiography demonstrated severe left ventricular dilatation with reduced ejection fraction (20%). Cardiac magnetic resonance imaging confirmed severe biventricular systolic dysfunction and revealed mid-to-basal myocardial fibrosis on late gadolinium enhancement imaging. Given the prominent multisystem involvement and exclusion of secondary causes, a syndromic cardiomyopathy was suspected. Comprehensive genetic testing identified likely pathogenic frameshift variants in the CD36 and TNXB genes, while additional variants of uncertain significance were detected in MT-TK and STXBP1. These findings suggested a potential oligogenic contribution involving pathways related to myocardial energy metabolism and extracellular matrix integrity. Guideline-directed medical therapy for heart failure with reduced ejection fraction was initiated, and the patient was enrolled in multidisciplinary follow-up with genetic counselling for first-degree relatives.

Discussion

This case highlights the limitations of a strictly monogenic framework in DCM and underscores the importance of considering oligogenic mechanisms in patients with syndromic features. Integrative evaluation combining detailed phenotyping, advanced cardiac imaging, and genetic analysis may provide valuable insights into complex cardiomyopathy phenotypes and support personalized clinical management.

Learning points.

• Multiple rare genetic variants may contribute to complex dilated cardiomyopathy (DCM) phenotypes beyond monogenic inheritance models.

• Syndromic findings such as neurological and musculoskeletal abnormalities may provide important clues for underlying genetic cardiomyopathy.

• Integrated interpretation of imaging, phenotypic findings, and genetic testing may help identify oligogenic contributions in DCM.

Introduction

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and sudden cardiac death and represents a major indication for heart transplantation. Traditionally, DCM has been considered as a predominantly monogenic disorder, most frequently attributed to pathogenic variants in sarcomeric or cytoskeletal genes such as TTN, LMNA, and MYH7. However, the widespread implementation of next-generation sequencing (NGS) has revealed a far more complex genetic landscape underlying DCM. Accumulating evidence suggests that a substantial proportion of patients harbour multiple genetic variants that collectively influence disease susceptibility and phenotypic expression. In this context, it is increasingly recognized that the genetic basis of DCM cannot be fully explained by single high-impact variants alone; rather, the cumulative effect of multiple genetic variants with individually modest effects may collectively contribute to disease susceptibility.¹ This paradigm shift has led to a progressive blurring of the boundaries between genetic and the so-called idiopathic DCM. Notably, in patients with accompanying neurological, musculoskeletal, or metabolic manifestations, DCM may present as part of a broader syndromic condition. In such cases, deep phenotyping and careful, context-driven interpretation of genetic findings are of critical importance. Herein, we present a case of syndromic DCM with multisystem involvement, in which likely pathogenic variants in the CD36 and TNXB genes—affecting myocardial energy metabolism and extracellular matrix integrity—may act synergistically to shape a severe clinical phenotype.

Summary figure

Case presentation

A 46-year-old male patient presented to our cardiology clinic with progressive dyspnoea lasting for 1 month, corresponding to the New York Heart Association (NYHA) functional class II–III. His medical history was notable for childhood-onset epilepsy, myopia and astigmatism, hiatal hernia, and hepatic steatosis. He had also been followed for infertility over the preceding 3 years. Family history revealed a paternal history of surgical repair for atrial septal defect; however, there was no reported history of cardiomyopathy or sudden cardiac death. On initial evaluation, lumbar lordosis, pectus carinatum, an ataxic gait, and a dysarthric speech pattern were evident (Figure 1). Vital signs were stable. Cardiac auscultation was unremarkable, while pulmonary examination revealed bilateral basal crackles. Moderate bilateral pretibial pitting oedema was present. Electrocardiography demonstrated sinus rhythm. Laboratory testing revealed elevated high-sensitivity cardiac troponin (58.63 ng/L; reference 0–14 ng/L) and NT-proBNP (3532 pg/mL; reference 0–132 pg/mL), with otherwise unremarkable routine biochemistry. Transthoracic echocardiography demonstrated severe left ventricular dilatation with a left ventricular ejection fraction (LVEF) of 20%, impaired right ventricular systolic function (TAPSE 1.35 cm), and an estimated systolic pulmonary artery pressure of 60 mmHg. Moderate mitral regurgitation and moderate-to-severe tricuspid regurgitation were also observed (Figure 2, Supplementary  Video 1). Coronary computed tomography angiography excluded ischaemic heart disease, demonstrating normal coronary anatomy and a calcium score of zero. At this stage, guideline-directed medical therapy for heart failure with reduced ejection fraction was initiated in accordance with contemporary European Society of Cardiology recommendations. Twenty-four-hour Holter monitoring revealed sinus rhythm with isolated premature atrial and ventricular beats, without sustained arrhythmias. To further investigate the aetiology, cardiac magnetic resonance (CMR) imaging revealed severe global biventricular systolic dysfunction (LVEF 22.4%) with dilatation of all cardiac chambers. Late gadolinium enhancement imaging demonstrated fibrosis involving the mid and basal anterior–inferior septal segments and the mid-to-basal lateral wall (Figure 3, Supplementary  Video 2). Given the prominent extracardiac manifestations, multidisciplinary evaluation was pursued. Neurological examination revealed ataxia, tremor, dysarthria, myoclonus, urinary incontinence, and a positive Romberg sign. Cranial magnetic resonance imaging demonstrated cerebral and cerebellar atrophy, ventriculomegaly, subcortical white matter hyperintensities, and partial empty sella. Electroencephalography showed epileptiform activity, and audiological assessment revealed bilateral sensorineural hearing loss. In light of the multisystem involvement and exclusion of secondary causes, a syndromic cardiomyopathy was suspected, and genetic counselling was requested. Comprehensive NGS using a cardiomyopathy gene panel identified several genetic variants. Variants in the mitochondrial MT-TK gene (m.8344A>G) and STXBP1 (c.936T>C, p.Ser312=) were classified as variants of uncertain significance. In contrast, a frameshift deletion in the CD36 gene (c.1202_1205del) and a frameshift duplication in the TNXB gene (c.8911_8912dup) were classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria, based on predicted loss-of-function effects (PVS1) and their rarity or absence in population databases (PM2). The TNXB variant was additionally supported by phenotypic concordance with the patient’s connective tissue manifestations (PP4) (Figure 4). Given the presence of severe left ventricular systolic dysfunction, the indication for a primary prevention implantable cardioverter–defibrillator was evaluated. However, as the patient had newly diagnosed non-ischaemic DCM, guideline-recommended reassessment after at least 3 months of optimized guideline-directed medical therapy was planned. Taken together, the genetic findings and multisystem involvement supported the interpretation of a syndromic cardiomyopathy with an oligogenic or polygenic basis. Integrative assessment of clinical, imaging, and genetic data indicated a complex phenotype not attributable to a single genetic mechanism. The patient remained under multidisciplinary follow-up, and first-degree relatives were referred for genetic counselling and consideration of family screening.

Figure 1.

Clinical phenotype and musculoskeletal findings of the patient. (A) Posterior view demonstrating the asthenic body habitus and subtle spinal curvature. (B) Lateral view highlighting the pectus carinatum deformity of the chest wall.

Figure 2.

Transthoracic echocardiography demonstrating severe left ventricular dilatation and markedly reduced left ventricular systolic function.

Figure 3.

Cardiac magnetic resonance imaging showing severe biventricular systolic dysfunction and late gadolinium enhancement in a mid-wall distribution involving the anterior–inferior septal segments and the lateral wall.

Figure 4.

Representative chromatograms of the identified genetic variants. (A) Heteroplasmic m.8344A>G variant in the MT-TK gene (55% VF), confirming the mitochondrial background. (B) Frameshift deletion (c.1202_1205del) in the CD36 gene, leading to a complex overlap pattern post-deletion, consistent with a loss-of-function effect.

Discussion

This case underscores the growing recognition of DCM as a genetically complex disorder, in which multiple variants—particularly in syndromic presentations—may contribute beyond a strictly monogenic framework. The decision to focus on the CD36 and TNXB variants was primarily driven by their classification as likely pathogenic according to ACMG criteria and their phenotypic relevance to the patient’s multisystem presentation. CD36 is involved in myocardial fatty acid uptake and energy metabolism, whereas TNXB plays a role in extracellular matrix organization and connective tissue integrity. Although no direct mechanistic interaction between these genes has been established, the coexistence of variants affecting distinct but potentially complementary biological pathways may contribute to phenotypic severity within an oligogenic framework. The likely pathogenic CD36 variant identified in this case raises a potential pathophysiological mechanism related to myocardial energy metabolism. CD36 encodes a transmembrane glycoprotein that plays a critical role in fatty acid uptake and energy production in cardiomyocytes. Disruption of this pathway has been implicated in myocardial energy imbalance, metabolic remodelling, and systolic dysfunction in both experimental and clinical studies. Available human genetic data and experimental evidence suggest that loss-of-function variants in CD36 may impair myocardial fatty acid uptake and energy utilization, potentially contributing to contractile dysfunction and a DCM phenotype in selected cases.² In addition, the likely pathogenic variant identified in the TNXB gene implicates a connective tissue–related pathway involving extracellular matrix integrity. As TNXB encodes tenascin-X and is associated with Ehlers–Danlos syndrome–like phenotypes, the patient’s pectus carinatum and musculoskeletal findings are phenotypically concordant. Although cardiac involvement is uncommon in TNXB-related disorders, impaired structural support may increase susceptibility to ventricular dilatation and systolic dysfunction, particularly under metabolic stress. Variants of uncertain significance were also identified in the MT-TK and STXBP1 genes. While the direct contribution of these variants to the observed cardiac phenotype cannot be clearly established, their potential modifying roles may be particularly relevant in patients with accompanying neurological and sensory manifestations. Clarifying the contribution of such variants requires integrated clinical–genetic correlation, supporting an oligogenic or polygenic model of DCM. While ACMG criteria are effective for high-penetrance Mendelian disorders, they have limitations in complex genetic architectures involving multiple rare variants. Accordingly, the variants identified in this case should be interpreted not as definitive causal determinants but rather as contextual, hypothesis-generating findings that suggest an oligogenic contribution when evaluated alongside the clinical phenotype.³ Importantly, the present case does not establish a direct mechanistic interaction between CD36 and TNXB, but rather highlights the possibility that multiple rare variants involving different biological pathways may collectively modulate disease expression and clinical severity in syndromic DCM. From a clinical perspective, this case emphasizes that DCM should not be regarded solely as an isolated cardiac condition, but rather considered within a broader syndromic and genetic context, particularly when accompanied by neurological, musculoskeletal, or sensory abnormalities. Although individual variants identified by NGS may lack diagnostic certainty in isolation, their integrated interpretation with detailed phenotyping and advanced imaging can provide insight into complex genetic architectures and inform multidisciplinary follow-up and genetic counselling. Nevertheless, the single-patient nature of this report, absence of segregation analysis, and lack of genetic testing in family members limit definitive causal inference. Accordingly, the findings should be regarded as hypothesis generating, highlighting the potential role of oligogenic interactions in dilated cardiomyopathy.

Lead author biography

Ipek Aydin, MD, is a cardiology resident at the Institute of Cardiology, Istanbul University–Cerrahpaşa. She received her medical degree from Marmara University School of Medicine (English programme). Her clinical interests include cardiomyopathies, heart failure, and advanced cardiovascular imaging, with a particular focus on the genetic and syndromic aspects of myocardial disease. She is actively involved in academic research and case-based publications, particularly within the European Society of Cardiology journal family, and participates in multidisciplinary clinical and research activities.

Supplementary material

Supplementary material is available at European Heart Journal – Case Reports online.

Author contributions

Ipek Aydin (Conceptualization, Investigation, Writing—original draft [lead], Writing—review & editing [equal]), Sevval Ilke Ebeoglu (Investigation [equal], Writing—review & editing [supporting]), Melike Kaya (Conceptualization, Investigation [supporting], Resources [equal]), Abdullah Omer Ebeoglu (Conceptualization [equal], Writing—original draft [supporting]), and Omer Dogan (Methodology, Supervision [lead], Writing—review & editing [supporting])

Consent: Written informed consent for publication was obtained from the patient in accordance with the Committee on Publication Ethics (COPE) guidelines. The patient reviewed the manuscript prior to submission and is aware of the potential implications of publication.

Funding

This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

All relevant clinical, imaging and genetic data are included within the manuscript.

Artificial intelligence declaration

During the preparation of this manuscript, the authors used generative artificial intelligence tools to assist with language refinement and clarity.

In addition, visual support tools were used during the design of the summary figure to enhance layout and graphical presentation.

All scientific content, figure concepts, and interpretations were developed, reviewed, and finalized by the authors, who take full responsibility for the accuracy and integrity of the work.