Abstract 16615: A Rare MEGF8 Variant is Involved in the Genetic Risk for Transposition of the Great Arteries

Abstract

Introduction: Transposition of the great arteries (TGA) is one of the most common neonatal heart defects with a prevalence of 0.2 per 1,000 live births. Although some studies have suggested laterality genes and environmental factors are involved, the pathogenesis of this outflow defect is still unclear. The majority of TGA are sporadic, arguing for a polygenic etiology. Methods: Whole exome sequencing (WES) analysis was conducted on 104 unrelated subjects with isolated or complex TGA. Variants in 20 human and mouse genes previously reported with TGA were recovered using frequency filter of 1%. These were compared to those on 120,000 subjects of the Genome Aggregation Database (GnomAD). Results: Among variants recovered in the 20 selected genes, we observed 14 (13.5%) patients with rare variants in MEGF8 . Four patients shared the same MEGF8 rare variant (0.26% in GnomAD) causing missense of a conserved amino acid (p.Val2502Ile). This variant is significantly overrepresented in the TGA cohort (OR=7.6, p =0.002). MEGF8 encodes a type I transmembrane protein shown to play a role in laterality specification in zebrafish and mice. It also has been shown to negatively regulate Hedgehog (Hh) signaling. Interestingly, recessive MEGF8 mutations are associated with Carpenter’s syndrome characterized by multiple congenital malformations and skeletal dysplasia. Unlike Carpenter’s mutations mostly distributed at the MEGF8 protein N-terminus, the variant we highlight is at the C-terminal extremity. Also of note, all TGA patients were heterozygous, except for one patient with cleft palate who had compound heterozygous MEGF8 mutations. Interestingly, 10 of the TGA patients also had rare variants in at least one other TGA-associated gene, supporting a complex genetic model of disease for TGA. Using fibroblasts from TGA patients with this variant and also Megf8 mutant mice with TGA, we are assaying Hh signaling pathway to confirm its role in TGA pathogenesis. Conclusions: We identified MEGF8 as a gene significantly associated with TGA, especially a rare variant localized at the C-terminus. The co-occurrence of rare variants in other laterality genes supports a multigenic etiology for TGA and points to the involvement of laterality defects in TGA pathogenesis.