The RIKADA Study: Next-Generation Sequencing of Pediatric Heart Failure Patients Identifies Novel Mutations in Cardiomyopathy Genes

Objectives: Pediatric heart failure is a severe, life-threatening condition that may result from genetically determined cardiomyopathy. Although the mechanisms leading to cardiomyopathy are well-established in adults, the underlying genetic mechanisms, early pathological events and further disease promoting factors are poorly characterized in children. To overcome this limitation the RIKADA study explores the clinical presentation, biochemical environment, and genetic status of index-patients and their first-degree relatives in-depth.

Method: The clinical presentation of pediatric index patients was assessed by MRI, echocardiography and spiroergometry in 38 index patients and their first-degree relatives. In addition, we performed mutational analysis of known cardiomyopathy genes with next generation sequencing (NGS).

Results: Mutations were detected in genes coding for sarcomere proteins such as cardiac muscle a-actin 1 (ACTC1), alpha 2 actinin (ACTN2), Lamin A/C (LMNA), and myosin heavy chain 7 (MYH7). Most frequently we found variants in the MYH7 gene (8 patients) and ACTN2 (2 patients). Novel mutations were identified in alpha-2 actinin (ACTN2) in a 6 year-old patient with left ventricular non-compaction (LVNC) and in LIM domain-binding protein 3 (LDB3) in a 19 year-old patient with hypertrophic cardiomyopathy (HCM).

Conclusion: Our accumulated data suggest that in-depth clinical phenotyping in combination with genetic analysis of index patients, affected and unaffected family members, is critical for reliable and predictive diagnosis.