Cardiogenetics

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.