A novel homozygous mutation in the TRDN gene causes a severe form of pediatric malignant ventricular arrhythmia

Abstract Background Triadin is a protein expressed in cardiac and skeletal muscle with an essential role in the structure and functional regulation of calcium release units and excitation-contraction coupling. Mutations in the triadin gene (TRDN) have been described in different forms of human arrhythmia syndromes with early onset and severe arrhythmogenic phenotype, among which the triadin knockout syndrome. Objective To characterize the pathogenetic mechanism underlying a case of severe pediatric malignant arrhythmia associated with defect in the TRDN gene. Methods We exploited trio whole exome sequencing approach to identify the genetic defect in a 2-years old boy with a resuscitated sudden cardiac arrest, frequent ventricular fibrillations and positive family history for sudden death. Then we performed in vitro functional analysis to investigate possible pathogenic mechanisms underlying this severe phenotype. Results We identified a novel homozygous missense variant (p.L56P) in the TRDN gene in the proband, inherited by the heterozygous unaffected parents. Expression of a GFP-tagged mutant human cardiac triadin isoform (TRISK32-L56P-GFP) in heterologous systems revealed that the mutation alters protein dynamics. Furthermore, when co-expressed with the type 2 ryanodine receptor, the caffeine-induced calcium release from TRISK32-L56P-GFP was relatively lower compared to that observed with wild type construct. Conclusions These evidences allowed to hypothesize a pathogenic mechanism underlying this rare arrhythmogenic recessive form, suggesting that the mutant protein can potentially trigger arrhythmias by altering calcium homeostasis.