RCAN family member 3 deficiency contributes to noncompaction of the ventricular myocardium

Abstract

Abstract Noncompaction of the ventricular myocaridium (NVM), as the third most commonly diagnosed cardiomyopathy, is characterized with highly variable clinical manifestations. Due to high heterogeneity, the genetic etiology of 40–60% NVM cases remains unknown. Here, we reported two infants of NVM in a non-consanguineous family with typically clinical presentation of persistent bradycardia since prenatal period. A homozygous missense mutation (R223L) of RCAN family member 3 (RCAN3) was detected in both infants by whole-exome sequencing. In the zebrafish model with rcan3 deficiency (MO-rcan3ATG-injected embryos), a marked lower heart rate without significant cardiac looping defects was detected in MO-rcan3ATG-injected embryos, which was similar to the NVM patients. Developmental dysplasia of both endocardial and myocardial layers were detected in zebrafish embryos with rcan3 deficiency. RCAN3 R223L variant mRNAs were unable to rescue heart defects caused by rcan3 knockdown. In rcan3-knockdown zebrafish model, several genes involved in cardiomyopathies were shown to be significantly regulated through multiple signaling pathways. This is the first report of RCAN3-related NVM in human. We suggest that RCAN3 as a novel susceptibility gene of cardiomyopathies, especially in NVM, while R223L variant was a potential loss-of-function variant.