Abstract MP212: Integrated Genomics Analysis Identifies Recessive Ciliopathy Mutations In Primary Endocardial Fibroelastosis: A Rare Neonatal Cardiomyopathy

Abstract

Background: Among neonatal cardiomyopathies, primary endocardial fibroelastosis (pEFE) remains a mysterious disease of the endomyocardium, affecting 1/5000 live births and accounting for 25% of the entire pediatric dilated cardiomyopathy (DCM) population with a devastating course and grave prognosis. Objective: We aimed to investigate potential genetic contributions to pEFE etiology. Methods: We performed integrative genomic analysis in 8 infants with confirmed pathological diagnosis of pEFE using whole exome sequencing (WES), RNA-seq and functional genomics studies. Patient-derived fibroblasts, neonatal rat ventricular myocytes and neonatal rat cardiac fibroblasts were used for cellular assays. Real-time cell migration and proliferation analyses were performed using xCELLigence technology. Results: Whole exome sequencing detected novel and deleterious de novo single nucleotide variants, or inherited homozygous rare variants in 11 cilia-related genes in seven out of the eight affected probands. In particular, a novel homozygous variant [c.1938delA] in ALMS1 was identified in a female proband, pEFE4. This variant resulted in a frameshift introducing a premature stop codon and complete absence of the ALMS1 protein in the proband fibroblasts and explanted heart. Loss of function mutations of ALMS1 have been implicated in Alstrom syndrome [OMIM 203800], a rare recessive ciliopathy. RNA-sequencing of the proband’s dermal fibroblasts revealed significantly dysregulated cellular signaling and function, including the induction of epithelial mesenchymal transition (EMT), potentially mediated by TGFβ signaling activation. The proband fibroblasts exhibited enhanced migration activity. Herein, we present the unique pathological features of pEFE compared to DCM and utilize integrated WES with RNA-seq analysis to elucidate the molecular mechanisms by which the novel causal ALMS1 variant contributes to the unique pathology of pEFE in a female infant with Alstrom syndrome. Conclusions: Our report provides insights into pEFE etiology and suggests, for the first time to our knowledge, ciliopathy as a potential underlying mechanism for this poorly understood and incurable form of neonatal cardiomyopathy.