Precision Medicine in Pediatric DCM: Genetic Insights and Clinical Applications

Abstract

Dilated cardiomyopathy (DCM) in children is a critical myocardial disease manifested by ventricular enlargement and depressed systolic performance, frequently complicated by heart failure, arrhythmias, thromboembolism, and sudden cardiac death. Pediatric DCM differs from adult DCM in having peculiar genetic heterogeneity, early age of onset, and rapid evolution. As techniques in genetic sequencing have improved, more than 100 DCM-associated genes have been recognized, mainly comprising calcium handling, cytoskeletal integrity, and ion channel function. The interaction between clinical phenotypes and genetic variants is still intricate, requiring a more profound understanding of genotype-phenotype relationships. This review examines the most recent studies on the genetic determinants of pediatric DCM, underlining the role of family-based genetic screening, novel molecular pathways, and precision medicine strategies. By incorporating genetic information into the clinical setting, early diagnosis and personalized therapies may enhance patient prognosis and disease control. Subsequent studies should be directed toward new gene discovery, functional validation, and genotype-directed risk stratification to improve precision medicine in pediatric DCM.

Introduction

Dilated cardiomyopathy (DCM) is the most prevalent form of cardiomyopathy in children and continues to be a major cause of heart failure, heart transplantation, and death. It is defined by left ventricular or biventricular enlargement with compromised systolic function, which precipitates a cascade of poor clinical outcomes including arrhythmias, sudden cardiac death, and thromboembolism. The genetic underpinnings of childhood DCM have attracted significant interest, with mounting evidence indicating a close association between genetic mutation and disease occurrence, severity, and course. In contrast to adult-onset DCM, in which the presentation tends to be insidious, childhood cases frequently involve acute clinical worsening and poor outcomes, requiring prompt detection and specific therapeutic interventions.

This article summarizes recent progress in genotype-phenotype studies in childhood DCM with an emphasis on the contribution of next-generation sequencing, genetic diversity, and personalized medicine to disease diagnosis, care, and prognosis.

Genetic Heterogeneity of Pediatric DCM

1. Genetic Basis of Pediatric DCM

DCM exhibits extensive genetic heterogeneity, with over 100 identified genes implicated in disease development. These genes primarily encode proteins involved in:

• Cytoskeletal Structure: Mutations in genes such as TTN (titin), LMNA (lamin A/C), and DES (desmin) impact sarcomere stability and myocardial integrity.

• Calcium Handling and Ion Channels: Genes like RYR2 (ryanodine receptor 2), SCN5A (sodium channel), and CASQ2 (calsequestrin 2) affect calcium homeostasis and electrical conduction, predisposing patients to arrhythmias.

• Mitochondrial Function: Mutations in MT-ATP6 and MT-TL1 disrupt energy production, contributing to progressive myocardial dysfunction.

2. Genotype-Phenotype Correlations

The interplay between genetic variants and clinical phenotypes is complex, with some mutations leading to severe, early-onset disease, while others result in milder forms. Key genotype-phenotype relationships include:

• LMNA-mutated DCM is associated with a high risk of conduction abnormalities and sudden cardiac death.

• TTN-truncating variants are linked to progressive myocardial dysfunction and increased transplantation rates.

• SCN5A mutations often manifest with overlapping arrhythmic syndromes, requiring tailored antiarrhythmic therapies.

Understanding these relationships is crucial for risk stratification, guiding surveillance strategies, and implementing early interventions.

Advances in Genetic Testing and Diagnosis

1. Next-Generation Sequencing (NGS) and Whole-Exome Sequencing (WES)

The advent of NGS and WES has revolutionized the diagnosis of genetic cardiomyopathies. These technologies enable:

• Rapid and comprehensive identification of pathogenic mutations.

• Early diagnosis in asymptomatic family members.

• Personalized risk assessment and genetic counseling.

2. Family-Based Genetic Screening

Due to the hereditary nature of DCM, screening family members of affected individuals is essential. Familial cosegregation studies help:

• Identify at-risk relatives before symptom onset.

• Determine inheritance patterns and guide reproductive planning.

• Implement preventive interventions for genotype-positive, phenotype-negative individuals.

Clinical Management and Therapeutic Approaches

1. Standard Heart Failure Management

Pediatric DCM treatment follows conventional heart failure management strategies, including:

• Pharmacologic Therapy: Beta-blockers, angiotensin-converting enzyme inhibitors (ACEi), and mineralocorticoid receptor antagonists to improve cardiac function.

• Device Therapy: Implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT) for arrhythmia management.

• Heart Transplantation: The definitive treatment for end-stage DCM with irreversible myocardial dysfunction.

2. Precision Medicine and Targeted Therapy

Integrating genetic insights into therapeutic strategies has paved the way for precision medicine. Emerging approaches include:

• Gene-Specific Interventions: Investigational therapies targeting specific mutations, such as RNA-based therapies for LMNA mutations.

• Pharmacogenomics: Individualized drug selection based on genetic predisposition to drug response and adverse effects.

• Stem Cell and Regenerative Therapies: Research into stem cell transplantation and gene editing techniques like CRISPR holds promise for disease modification.

Challenges and Future Directions

Despite significant advancements, several challenges remain in the field of pediatric DCM genetics:

• Incomplete Genetic Penetrance: Not all individuals with pathogenic mutations develop DCM, indicating the influence of epigenetics and environmental factors.

• Limited Therapeutic Options: While genetic screening improves diagnosis, targeted treatments remain largely experimental.

• Need for Large-Scale Studies: More extensive cohort studies are needed to validate genotype-phenotype associations and refine risk prediction models.

Future research should focus on:

• Discovering novel pathogenic genes and mutations.

• Enhancing functional validation of identified variants.

• Developing gene-based therapies and personalized treatment strategies.

Conclusion

Pediatric DCM is a genetically heterogeneous disorder with intricate genotype-phenotype correlations. Evolution in genetic studies and DNA sequencing technology has improved diagnostic tools to enable early detection and risk stratification of those with the condition. However, translating genetic data into specific therapies is still problematic. A multidisciplinary model, where genetic information is combined with clinical management, is the way forward in ensuring better outcomes for children with DCM. Through ongoing investigation of new genetic determinants and the creation of precision medicine approaches, pediatric DCM care will become progressively personalized and successful in the future.

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