Abstract P1182: The Genetic Dissection Of Rpl3l As A Causal Gene For Neonatal Dilated Cardiomyopathy And Left Ventricular Noncompaction

Background: Cardiomyopathies are responsible for nearly 10% of cardiac deaths in neonates. Recently, biallelic variants in ribosomal protein L3-like ( RPL3L , NM_005061.2) have been reported in neonates with dilated cardiomyopathy (DCM) and heart failure (HF). This study is aimed to study RPL3L induced genetic pathways and mechanisms involved in the development of DCM. Methods: Whole exome and RNA sequencing, histology, immunohistochemistry, and Western blotting were performed in a human explanted heart. Genetic correlation, expression quantitative trait loci (eQTL) mapping and functional analysis were performed using cardiac gene expression data from the patient as well as human and murine genetic reference populations (GRPs). Results: Two-month-old patient with DCM and HF carrying compound heterozygous RPL3L variants, p.A51T and p.V231F, has been managed on an INTERMACS profile 2 with continuous-flow ventricular assist device and successfully bridged to heart transplantation at the age of 4 months. Morphology of the explanted heart displayed apical deep intertrabecular recesses consistent with left ventricular noncompaction (LVNC). Histology revealed interstitial fibrosis and myocardial hypertrophy. No signs of myocarditis and glycogen or mucopolysaccharides deposits were detected. Immunohistochemistry revealed abnormal clusters of RPL3L protein in the cytosol of cardiomyocytes and disruption of F-actin, Z-disk proteins, MYL4 and dystrophin was evident. In a mouse heart, the Rpl3l level was of 33.45 RPKM, while levels of RPL3L appeared to be 32 RPKM in a human heart compared to its mean expression in other adult tissues of 2.54 (mouse) and 2.36 (human). Systems genetics analysis identified high expression values ranged from 11.31 to 12.16 across murine GRPs of BXD mice with the ~1.8-fold difference. Pathways such as “thermogenesis”, “diabetic cardiomyopathy” and “DCM” significantly associated with RPL3L. e QTL mapping suggested Myl4 (Chr 11) and Sdha (Chr 13) as the upstream regulators of Rpl3l . Conclusions: Compound RPL3L heterozygosity is causal for neonatal DCM and LVNC. The RPL3L is highly expressed in the heart tissue of humans and mice. Genes, Myl4 and Sdha, are strong candidates that regulate expression of Rpl3l in murine heart.