Congenital heart defects (CHDs) are the most common congenital anomalies, with identifiable genetic etiologies in approximately 5-30% of affected infants, depending on the clinical presentation and comorbidities. This study included 216 children with CHD, predominantly syndromic, to explore the role of genetic variants in their morphological phenotypes. Chromosomal microarray (CMA) and whole-exome sequencing (WES) were performed, revealing clinically significant copy number variations (csCNVs) in 59 (27.3%) patients. The most frequent were 22q11.21 (8/59; 13.6%) and 7q11.23 (5/59; 8.5%) deletions. WES was conducted in 28.0% of cases, achieving a detection rate of 29.5%, primarily identifying variants related to Noonan syndrome. Genetic diagnoses were confirmed in 33.3% of patients, with clinically significant CNVs and SNV/INDELs found exclusively in those with syndromic CHD, leading to a 36.5% diagnosis rate in those patients. The identified variants most frequently affected genes encoding transcription factors (40.4%), followed by genes involved in the RAS signaling pathway and structural proteins (17.0%), and chromatin remodeling proteins (12.8%).
Background: Genetic testing in hypertrophic cardiomyopathy (HCM) yields variable positivity rates. Identifying clinical predictors of positive genetic tests could improve pre-test counseling and refine expectations about diagnostic yield. Methods: We analyzed consecutive genotyped HCM probands from a contemporary multicenter cohort across four Italian tertiary centers. Genotype positivity was defined as the presence of >= 1 pathogenic or likely pathogenic variant (ACMG classes 4-5). Multivariable logistic regression identified predictors of genotype positivity. Sensitivity analyses assessed the incremental value of left atrial volume index (LAVI) >= 34 mL/m(2) and the mode of first clinical presentation. Results: Among 274 genotyped probands (median age at diagnosis 54 years; 62% male), 86 (31%) were genotype-positive (38% MYBPC3, 29% MYH7). Age at diagnosis <40 years (OR 2.38, 95%CI 1.26-4.51, p = 0.008), family history of sudden cardiac death/major ventricular arrhythmias (OR 2.34, 95%CI 1.16-4.84, p = 0.019) and family history of non-ischemic cardiomyopathy (OR 1.92, 95%CI 1.04-3.54, p = 0.038), were independently associated with genotype positivity whereas arterial hypertension was inversely associated (OR 0.42, 95%CI 0.23-0.77). Maximal left ventricular wall thickness > 20 mm and gender were not predictive of genotype positivity. Inclusion of LAVI modestly improved the model performance (AUC 0.769, p = 0.016, Delta AUC +0.024; DeLong p = 0.016) but without leading to meaningful patient reclassification. Conclusions: Genotype positivity in HCM links to earlier onset and family history; traditional severity markers and initial presentation may not independently suggest genetic causality. These findings may help shape a personalized approach to genetic counseling in HCM.
Background: Heterozygous familial hypercholesterolemia (HeFH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased cardiovascular risk, making early diagnosis essential; however, the diagnostic performance of pediatric criteria is heterogeneous. This study evaluated the effectiveness of different diagnostic criteria and scoring systems to select children for genetic testing. Materials and methods: A total of 214 pediatric subjects with suspected HeFH were included, recruited from patients followed at a tertiary care center, based on LDL-C levels >= 95th age- and sex-specific percentile in both the proband and one biological parent. All subjects underwent genetic analysis of the main FH-associated genes (LDLR, APOB, PCSK9). The following diagnostic criteria and scoring systems were retrospectively evaluated and compared with genetic findings: Simon Broome Register (SBR), Dutch Lipid Clinic Network (DLCN), European Atherosclerosis Society (EAS), American Heart Association (AHA), Familial Hypercholesterolemia Canada Network (FH-CAN), Japanese Atherosclerosis Society (JAS), Lipid TransPort Disorders Italian Genetic Network for Italian pediatric patients (LIPIGEN-FH-PED), and the Familial Hypercholesterolemia Pediatric Diagnostic Score (FH-PeDS). Results: Pathogenic variants were identified in 91.8% of subjects. Approaches using lower LDL-C thresholds minimized the loss of variant-positive individuals (particularly JAS and FH-PeDS, with a missed diagnoses rate of 1.6%), whereas more restrictive definitions excluded a substantial proportion of affected patients (10.5% SBR, 56.3% DLCN, 6.3% EAS, 6.3% AHA, 7.4% FH-CAN, and 6.3% LIPIGEN-FH-PED). The mutation detection rate (MDR) was >91% for all examined criteria. Conclusions: Several current diagnostic criteria may underestimate the true number of children carrying FH-associated variants. Less selective criteria enable the identification of a greater number of FH-positive individuals while maintaining a high MDR, thus supporting the prioritization of identifying as many affected children as possible in the pediatric setting. This cohort reflects a tertiary referral population rather than the general population; therefore, further studies are needed to evaluate the applicability of our findings to broader public health contexts and screening settings.
Endocrine disorders are increasingly recognized as major contributors to secondary cardiomyopathies, leading to profound alterations in cardiac structure and function. This comprehensive review synthesizes current evidence on the genetic basis of cardiomyopathies associated with endocrine conditions, including primary aldosteronism, Cushing’s syndrome, pheochromocytoma/paraganglioma, acromegaly, thyroid disorders, hyperparathyroidism, and diabetic cardiomyopathy. We examine the contribution of somatic and germline mutations, genetic polymorphisms, shared molecular pathways transforming growth factor-β (TGF-β)/SMAD (TGF-β/SMAD signaling, the renin–angiotensin–aldosterone system, oxidative stress, and calcium handling), sarcomeric gene modifiers, ion channel variants, and epigenetic mechanisms to disease pathogenesis. We propose a conceptual framework distinguishing three major categories of genetic involvement: (i) variants causing the primary endocrinopathy; (ii) genetic modifiers of myocardial susceptibility under conditions of hormonal excess; and (iii) direct pleiotropic effects, whereby single gene variants independently cause both endocrine and cardiac phenotypes. In addition, we discuss genotype–phenotype correlations, ethnic and population differences in genetic susceptibility, the emerging role of polygenic risk scores, and precision medicine approaches. Overall, this review provides an integrated perspective on the complex genetic architecture of endocrine-related cardiomyopathies and outlines practical considerations for genetic testing aimed at improving patient management and clinical outcomes.
Noonan syndrome (NS) is a paradigmatic rare, genetically heterogeneous, multisystem disorder belonging to the RASopathies family, caused by dysregulated RAS/MAPK signaling. It is characterized by distinctive craniofacial features, postnatal short stature, and a high prevalence of congenital cardiac defects, with pulmonary valve stenosis (PS) and hypertrophic cardiomyopathy (HCM) being the hallmark lesions. First described by Dr. Jacqueline Noonan in 1968, the molecular era began with the discovery of PTPN11 mutations in 2001, revolutionizing diagnosis, risk stratification, and understanding of pathogenesis. Strong genotype–phenotype correlations now guide prognosis and personalized management; for instance, RAF1 and RIT1 variants confer a high risk of severe, early-onset HCM, while PTPN11 is strongly linked to dysplastic PS. Cardiac involvement remains the central determinant of long-term outcomes, requiring continuous surveillance from the prenatal period through adulthood. Management is inherently multidisciplinary, addressing endocrine, hematologic, neurodevelopmental, and oncologic aspects. Recent consensus statements emphasize the critical need for structured transition from pediatric to adult care. Novelty arises from the potential of MEK inhibitors as targeted therapies for severe HCM and lymphatic complications. This review provides a comprehensive update on NS, integrating foundational clinical knowledge with contemporary molecular insights, advanced cardiologic management, and emerging frontiers in therapy and diagnostics, underscoring the necessity of a proactive, lifelong, and personalized care approach.
In this study, we have performed computational PTM analysis on a panel of hypertrophic cardiomyopathy (HCM)-associated proteins: MYH7, MYBPC3, TNNT2, and TNNI3. We aimed to benchmark the prediction of PTM sites of three ML-based tools: MusiteDeep, PTMGPT2, and SiteTack, using PhosphoSitePlus as a reference for true positives. Notably, because the highest precision tool varied by protein and PTM type, our results indicate there is no single best tool for PTM prediction. Specifically, for HCM-associated proteins, MusiteDeep had the highest precision for MYBPC3 and MYH7; PTMGPT2 was best for TNNI3, and SiteTack for TNNT2. Examining PTM type and phosphorylation in particular, MusiteDeep had the highest precision, followed by PTMGPT2 and SiteTack. However, MusiteDeep did not identify acetylation sites, where PTMGPT2 outperformed SiteTack. Beyond these benchmarking results, we also report on five high-priority candidates for experimental validation in two HCM-associated proteins: MYH7 (K1451 acetylation, K129 methylation) and MYBPC3 (T705 phosphorylation, K14 acetylation, R44 methylation).
Background: PRKAG2 cardiac syndrome is a rare autosomal dominant glycogen-storage cardiomyopathy that mimics sarcomeric hypertrophic cardiomyopathy (HCM) but features ventricular pre-excitation, progressive conduction disease and concentric hypertrophy due to intracellular glycogen accumulation. The c.905G>A (p.Arg302Gln) variant is one of the most frequently reported pathogenic substitutions. Case summary: We describe a three-generation family carrying the heterozygous PRKAG2 p.Arg302Gln variant. The proband, a 41-year-old man, presented with paroxysmal atrial fibrillation, short PR interval and abnormal intraventricular conduction associated with concentric left ventricular hypertrophy and preserved ejection fraction. Holter monitoring disclosed episodes of high-grade atrioventricular block, prompting implantation of a primary-prevention dual-chamber ICD. Two gene-positive brothers exhibited milder hypertrophy but shared sinus bradycardia, ventricular pre-excitation and supraventricular arrhythmias; one underwent catheter ablation of a posteroseptal accessory pathway. The affected mother displayed a hypertrophic phenotype complicated by sick sinus syndrome and permanent atypical atrial flutter requiring pacemaker implantation. No relevant extracardiac involvement was detected in any family member. Review and novelty: Using this family as a starting point, we provide a concise narrative review of PRKAG2 syndrome with emphasis on the Arg302Gln genotype, molecular mechanisms and emerging treatment strategies. We highlight key multimodality imaging and tissue-characterization features that help distinguish diffuse, concentric glycogen-storage hypertrophy from the often-asymmetric pattern of sarcomeric HCM. Integration of our findings with published Arg302Gln cohorts illustrates the broad phenotypic variability in conduction disease, pre-excitation and atrial arrhythmias. Conclusions: PRKAG2 p.Arg302Gln-related cardiomyopathy should be suspected in patients with otherwise unexplained left ventricular hypertrophy associated with short PR interval, pre-excitation or early brady–tachy arrhythmias. Early recognition of red-flag features, systematic genetic testing, family screening and tailored arrhythmia/device management are crucial, while emerging gene- and pathway-targeted therapies may offer future disease-modifying potential.
Mitral annular disjunction (MAD) is associated with an increased risk of ventricular arrhythmias and sudden cardiac death, yet its genetic background remains poorly defined. We report the case of a 50-year-old man with MAD who survived cardiac arrest and carries three variants of unknown significance (VUS) in genes involved in cardiomyopathy pathogenesis. To explore the genetic basis of non-syndromic MAD, we performed a systematic review of the literature, identifying five case reports and one retrospective cohort study. The case reports described patients with MAD harboring four pathogenic variants and ten VUS. Two pathogenic variants were linked to cardiomyopathies, involving proteins of the nuclear envelope and cytoskeleton, while two were associated with channelopathies. The retrospective cohort study identified a recurrent variant in a gene involved in intercellular adhesion segregating within a family affected by MAD. Overall, available evidence suggests that genetic factors may hypothetically modulate susceptibility to MAD, not only in connective tissue disorders but also in isolated mitral valve disease. Variants associated with arrhythmogenic cardiomyopathies and channelopathies appear to cluster in families with non-syndromic MAD and arrhythmic phenotypes, suggesting a role in the arrhythmic substrate. However, in absence of definitive functional, segregation, or longitudinal data, the contribution of genetic variants to MAD should be interpreted with caution. Further genomic studies are needed to clarify their genetic contribution and prognostic implications.
Background/Objectives: Coronary artery disease (CAD) remains the leading cause of mortality worldwide, with South Asia bearing a disproportionately high and rising burden, particularly at younger ages. The present study aimed to investigate genetic variants associated with premature coronary artery disease (PCAD) using whole-genome sequencing (WGS). Methods: WGS was conducted on 12 people (five PCAD cases, seven matched controls) to assess feasibility and methodology for future large-scale research. High-quality genomic DNA was sequenced at a minimum read depth of 10 & times; with a quality threshold of Q30. Variant calling with stringent quality control identified single-nucleotide polymorphisms (SNPs), followed by annotation against gnomAD for allele frequencies and ClinVar for pathogenicity. Protein-coding variants were filtered, and candidate genes were prioritized for comparative analysis between cases and controls. Results: An average of over 8.8 million SNPs per individual was identified, with comparable overall variant distributions between cases and controls. Initial analyses revealed 120 SNPs exclusively present in PCAD cases. All protein-coding variants were rare (allele frequency < 0.0001), and none were previously classified as pathogenic in ClinVar. After filtration, 87 candidate genes were prioritized. Enriched or unique variants in PCAD cases are mapped to genes involved in lipid metabolism, endothelial dysfunction, inflammatory signaling, immune regulation, thrombosis, vascular remodeling, and metabolic processes. Additional variants were identified in genes related to smooth muscle proliferation, oxidative stress, and other biological pathways. Conclusions: This WGS pilot study provides an initial overview of the genomic landscape of PCAD in a South Asian cohort, highlighting rare variants across multiple biological pathways implicated in atherosclerosis that need validation in a large-scale study.
Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disorder, is usually caused by pathogenic variants in sarcomeric genes and is inherited in an autosomal dominant manner. Around 5% of cases are caused by variants in non-sarcomeric genes, which may involve alternative modes of inheritance. This study presents the first reported case of HCM associated with digenic contribution of heterozygous variants in two non-sarcomeric genes: ALPK3 and TRIM63. The patient was incidentally diagnosed with non-obstructive HCM in childhood and developed extreme myocardial hypertrophy with moderate heart failure at the age of 18. Rapid progressive left ventricular dysfunction promptly resulted in death at the age of 26. Genetic testing with an extended HCM panel identified no sarcomeric variants but revealed two truncating variants in the ALPK3 and TRIM63 genes. Whole-genome sequencing excluded any other causes of the disease. Heterozygous ALPK3 variants are typically associated with late-onset HCM, whereas TRIM63 variants are only considered pathogenic in a recessive state. This case, therefore, suggests a synergistic contribution of both variants to the development of a severe phenotype. The potential mechanisms of interaction between the protein products of ALPK3 and TRIM63 within the M-band of the sarcomere are discussed.
Arrhythmogenic cardiomyopathies (ACMs) are a phenotypically and etiologically heterogeneous group of myocardial disorders characterized by fibrotic or fibro-fatty replacement of ventricular myocardium, electrical instability, and an elevated risk of sudden cardiac death. Initially identified as a right ventricular disease, ACMs are now recognized to include biventricular and left-dominant forms. Genetic causes account for a substantial proportion of cases and include desmosomal variants, non-desmosomal variants, and familial gene-elusive forms with no identifiable pathogenic mutation. Nongenetic etiologies, including post-inflammatory, autoimmune, and infiltrative mechanisms, may mimic the phenotype. In many patients, the disease remains idiopathic despite comprehensive evaluation. Cardiac magnetic resonance imaging has emerged as a key tool for identifying non-ischemic scar patterns and for distinguishing arrhythmogenic phenotypes from other cardiomyopathies. Emerging classifications propose the unifying concept of scarring cardiomyopathies based on shared structural substrates, although global consensus is evolving. Risk stratification remains challenging, particularly in patients without overt systolic dysfunction or identifiable genetic markers. Advances in tissue phenotyping, multi-omics, and artificial intelligence hold promise for improved prognostic assessment and individualized therapy.
Danon Disease (DD) is a rare X-linked autophagic vacuolar myopathy caused by pathogenic variants in the lysosome-associated membrane protein 2 (LAMP-2) gene. Alternative splicing of the terminal exon 9 leads to the creation of three different isoforms, each with essential roles in regulating autophagy. DD is characterized by cardiomyopathy, skeletal myopathy, cognitive impairment, and retinal disorders, with cardiac involvement being the primary cause of morbidity and mortality. Muscle biopsy may reveal signs of vacuolar myopathy, but the diagnosis is typically confirmed through sequencing and deletion/duplication analysis of the LAMP-2 gene using peripheral blood. Although few genotype–phenotype correlations have been described, with most being limited to isoform 2B of exon 9, the most significant prognostic indicator remains sex. The disease manifests earlier and with a more severe systemic presentation in males due to their hemizygous status, whereas in females, the typical presentation is late-onset hypertrophic or dilated cardiomyopathy, generally without extracardiac involvement. Cases of severely affected women have been described, potentially due to non-random or defective X-inactivation. The less typical and delayed clinical presentation in females can result in incorrect or missed diagnoses. The aim of this narrative review is to summarize the natural history, diagnostic criteria, management strategies, and recent advancements in the understanding of DD in women.
Introduction: Clinical variability within families harbouring disease-causing genetic variants hampers clinical care and risk stratification. We studied a multigenerational family presenting with sinus bradycardia and long QT syndrome type 2 (LQTS2). The family harboured a pathogenic variant in KCNH2, which co-segregated with the observed LQTS2. We studied the genetic cause of the high occurrence of sinus bradycardia in this family. Methods: Clinical data was collected, including heart rate, QT-interval, symptoms, and echocardiographic parameters. QTc was calculated using the Bazett and the Fridericia formula. Sanger sequencing of HCN4 was performed, followed by segregation analysis of the identified variant with sinus bradycardia. The biophysiological consequences of two variants, KCNH2-p.L69P (c.206T>C) and HCN4-p.R666W (c.1996C>T), were assessed by patch-clamp experiments. Therefore, a heterologous model was generated by transfection of HEK293A or CHO-k1 cells, respectively. Results: Sanger sequencing of HCN4 identified HCN4-p.R666W (c.1996C>T), which has a stronger segregation with the observed sinus bradycardia than KCNH2-p.L69P. Patch-clamp experiments revealed that KCNH2-p.L69P and HCN4-p.R666W lead to a decrease in the corresponding current densities, which explains the LQTS and sinus bradycardia observed in the patients. Carriers of both genetic variants have a more severe LQTS2 phenotype, reflected in longer QT and higher incidence of syncope. Conclusions: We identified two (likely) pathogenic variants, KCNH2-p.L69P and HCN4-p.R666W, co-segregating with LQTS2 and sinus bradycardia, respectively. Patients carrying both variants showed a more severe phenotype. These findings highlight the importance of additional genetic testing when discordant features are present, thereby enabling more accurate diagnosis, risk prediction, and management.
Background: PRKAG2-related disease is an autosomal dominant disorder caused by pathogenic variants in the PRKAG2 gene, leading to glycogen accumulation in cardiomyocytes. It is characterized by left ventricular hypertrophy (LVH), ventricular pre-excitation, and conduction disease. Due to the rarity of the condition and the frequent occurrence of private variants, functional or pathological testing is required for definitive pathogenicity classification. Case Presentation: We describe a 22-year-old male referred for evaluation after experiencing exertional dyspnea and a syncopal episode. Family history revealed sudden cardiac deaths and conduction disease requiring pacemaker implantation. The patient exhibited mild LVH on imaging, conduction abnormalities on electrophysiological study, and a heterozygous PRKAG2 variant (c.1643C>T; p.Ser548Leu), classified as likely pathogenic according to ACMG guidelines. Cascade screening identified the variant in three family members, one of whom exhibited a positive phenotype. Endomyocardial biopsy revealed glycogen accumulation, providing histopathological confirmation of PRKAG2-related disease. Conclusions: This case underscores the importance of integrating genetic, clinical, and histopathological data in variant interpretation. Endomyocardial biopsy can provide definitive evidence to reclassify a PRKAG2 variant as pathogenic, thereby guiding management and family screening.
Background: Regular endurance training induces physiological changes in cardiac structure and function. The precise epigenetic mechanisms by which cardiovascular adaptations are mediated are still unclear. This review seeks to clarify the role of epigenetic regulation in exercise-induced cardiovascular adaptation. Methods: This systematic review was conducted in accordance with the PRISMA guidelines up to 30 April 2025, using the databases PubMed, VHL, and LILACS Plus. Studies were included if they focused on microRNA expression and DNA methylation in individuals with cardiovascular disease who underwent endurance training. Results: Six articles, including 384 participants with heart failure, coronary artery disease, and hypertension, were included in the final analysis. Changes in DNA methylation and microRNA expression of specific genes involved in cardiovascular structural and functional adaptation were observed. Significant improvements were found in body composition, VO2peak, systolic and diastolic blood pressure, and left ventricular function and structure. Conclusions: Endurance training has a positive impact on epigenetic mechanisms related to cardiovascular structural and functional adaptation. A clear causal link between epigenetic modifications and clinical outcomes remains to be established.
Congenital genetic heart defects are major contributors to pediatric morbidity and mortality, underscoring the importance of early detection and individualized therapeutic strategies. This review aimed to summarize current knowledge on a spectrum of inherited cardiovascular disorders, with a focus on their genetic etiology, molecular pathogenesis, and phenotypic presentation in children. Conditions discussed include Marfan syndrome, Noonan syndrome, various cardiomyopathies, Duchenne muscular dystrophy, DiGeorge syndrome, and the tetralogy of Fallot. These six conditions were selected to represent the spectrum of pediatric cardiovascular genetic diseases, encompassing connective tissue disorders, multisystem syndromes, primary myocardial diseases, neuromuscular cardiac involvement, and structural congenital defects, thereby illustrating how distinct genotypes lead to diverse phenotypes. For each disorder, the underlying genetic mutations, associated molecular pathways, cardiovascular involvement, clinical features, and approaches to diagnosis and management are examined. Emphasis is placed on the role of timely diagnosis, genetic counseling, and personalized treatment in improving patient outcomes. The review concludes by highlighting emerging research directions and novel therapeutic interventions aimed at enhancing care for these complex pediatric conditions.
Background: Polygenic risk scores (PRSs) aggregate the effects of many common genetic variants and are being investigated as tools to refine coronary artery disease (CAD) risk prediction beyond traditional clinical models. Methods and Results: We review the development of PRS from early unweighted scores to contemporary genome-wide models and summarize evidence from major studies. We identified key studies through PubMed searches using the terms “polygenic risk score,” “genetic risk prediction,” and “coronary artery disease,” supplemented by citation chaining of highly cited articles and recent reviews. Large cohorts, such as the UK Biobank, show that individuals in the highest PRS percentiles have a 3–5-fold higher risk of CAD, and may gain the greatest benefit from statin therapy. PRS can also reclassify younger adults at borderline or intermediate risk and may complement coronary artery calcium (CAC) scoring. Conclusions: PRSs hold promise for lifetime risk stratification and targeted prevention in CAD but are limited by ancestry bias in GWAS, underrepresentation of diverse populations, inconsistency in individual estimates, and lack of standardized reporting. Future research should focus on expanding multi-ancestry databases, standardizing methods, prospective validation, and effective communication strategies to support equitable and evidence-based clinical use.
Dystrophinopathies, including Duchenne and Becker muscular dystrophies (DMD and BMD), are inherited neuromuscular disorders frequently complicated by progressive cardiac involvement, ultimately leading to advanced heart failure. While heart transplantation and long-term left ventricular assist device (LVAD) therapy represent potential therapeutic options, their application in this population raises significant ethical challenges. This review explores the ethical implications surrounding the allocation of scarce medical resources, particularly in patients with limited life expectancy and multisystem disease, as in DMD. Decisions regarding eligibility for heart transplantation must balance individual benefit, considering the impact of excluding other potential recipients. LVAD therapy, although more accessible, still demands careful patient selection due to high perioperative risk and postoperative complications. The review emphasizes the need for transparent, multidisciplinary decision-making processes that respect patient autonomy while ensuring equitable and rational distribution of healthcare resources. Ultimately, while advanced therapies may be feasible in selected cases, particularly in BMD, ethical deliberation remains central to determining their appropriateness in the context of dystrophinopathies.
This study investigates the genetic background of pediatric-onset cardiac channelopathies, a rare group of genetic disorders causing arrhythmias and sometimes sudden death, whose genetic background remains partially unknown. The research analyzed 59 pediatric patients (<18 years of age) diagnosed with different channelopathies (LQTS, BrS, CPVT, SQTS, and conduction disorders), along with 40 of their family members, using Next-Generation Sequencing (NGS) after genetic counseling. A causative genetic variant was found in 47% of cases, mainly in the KCNQ1 (42%), RYR2 (16%), CACNA1C (10%), and SCN5A (10%) genes. Notably, a de novo large deletion in KCNH2 was detected in an LQTS patient, and a pathogenic CALM1 variant was identified in a child. A compound heterozygous KCNQ1 was consistent with Jervell and Lange-Nielsen syndrome. In light of these data, genetic testing is crucial for diagnosis, prognosis, and treatment planning; cascade screening allowed early risk identification and preventive interventions for family members. Expanding NGS technologies and research on new candidate genes may enhance personalized therapies in the future.
Background: Ebstein’s anomaly (EA) is a rare congenital heart defect characterized by failure of tricuspid valve delamination during embryogenesis. Left ventricular (LV) hypertrabeculation results from incomplete myocardial compaction during fetal development. EA is associated with LV hypertrabeculation in 0.14% of cases, and EA is the most common congenital heart disease in LV hypertrabeculation (up to 29%), suggesting a shared embryogenetic pathway. Case Report: We describe a female patient prenatally diagnosed with EA and a large ventricular septal defect. Postnatal echocardiography confirmed EA with moderate regurgitation and revealed previously unnoticed left ventricular excessive trabeculations. Whole exome sequencing revealed a heterozygous never-described variant of unknown significance in the TNNC1 gene. Discussion: The genetic link between EA and LV hypertrabeculation remains unclear, though variants in sarcomeric or cytoskeletal genes like MYH7, TPM1, and NKX2.5—essential for cardiac development—have been implicated. A developmental hypothesis suggests that aberrant contraction during endocardial-to-mesenchymal and epicardial-to-mesenchymal transformation (5th–8th gestational weeks) may affect valve delamination and ventricular compaction via parallel signaling pathways. TNNC1 encodes troponin C1, a subunit of the troponin complex involved in muscle contraction. Its mutations are known to alter calcium sensitivity and impair cardiac contractility. Conclusions: EA and LV hypertrabeculation patients diagnosed in infancy have a greater risk of negative outcomes. Early, especially prenatal, diagnosis is crucial. Genetic analysis can provide fundamental insight into cardiac development. This new and rare variant of TNNC1 gene supports the hypothesis that early cardiomyocytes dysfunction disrupts both valve delamination and left ventricular compaction and that the two diseases share a common genetic pathway related to cardiomyocyte contraction.
