Abstract 18895: A Novel Gene Involved in Severe Neonatal Cardiomyopathy

Cardiomyopathies (CMP) in children are heterogeneous disorders of cardiac muscle with a relatively high incidence in infancy (8/100.000) as compared to older children (0.7/100.000). Beyond infancy, CMP is the most important indication for heart transplantation and transplantation free survival at 5 years after initial diagnosis is only 54%. Mutations in over 65 genes encoding sarcomeric, cytoskeletal and calcium-metabolizing proteins, cell-signaling molecules, and mitochondrial enzymes have been shown to cause CMPs. This has led to new recommendations for diagnostic evaluation and family screening incorporating genetic testing. However, present (targeted/custom based) diagnostic tests do not represent the whole spectrum of genetic etiologies and are leading to a correct diagnosis in just a subset of pediatric CMP patients. We present four children from two consanguineous families of Dutch and Moroccan descent with severe neonatal onset of CMP, ranging from lethal cardiomegaly with reduced contractility in three to severe left ventricular hypertrophy that remained stable in one child. A combined approach using homozygosity mapping and exome sequencing in both families identified a homozygous splice site variant resulting in exon skipping in the Dutch family, and a homozygous nonsense mutation in the Moroccan family within the same gene. This novel disease causing gene is implicated in the early differentiation of cardiomyocytes. Both variants were confirmed with Sanger sequencing and absent in large control populations. Previously published studies in a knockout mouse model demonstrated the functional role of this gene in CMPs. Additionally, we investigated the effect of the homozygous splice site mutation on the expression of different proteins at myocardial cell-cell junctions and myofibrils. These results point towards a role in intercalated disk remodeling. Electron microscopy- and protein expression studies on heart tissue of the patients are ongoing. Our findings add a new autosomal recessive gene to the list of genes already implicated in pediatric CMP, underscoring its genetic heterogeneity. Furthermore, our study indicates that the application of exome sequencing can improve the diagnostic yield in pediatric CMP.