Novel cases of pediatric sudden cardiac death secondary to TRDN mutations presenting as long QT syndrome at rest and catecholaminergic polymorphic ventricular tachycardia during exercise: The TRDN arrhythmia syndrome

Abstract

TRDN mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT) but may present with abnormal electrocardiogram (ECG) findings provoking a diagnosis of long QT syndrome (LQTS). We report two novel cases of sudden cardiac death in children due to mutations of TRDN, providing further insight into this rare and aggressive inherited arrhythmia syndrome. Whole exome sequencing (WES) was performed in two unrelated children who experienced cardiac arrest during exercise and were negative for targeted testing of LQTS. WES identified a novel homozygous splice‐site mutation in both patients, denoted c.22+1G>T, absent from gnomAD and suggesting a founder variant in the Iranian population. We now summarize the genetic architecture of all reported TRDN‐related patients, including 27 patients from 21 families. The average age‐onset was 30 months (range 1–10) for all cases. Adrenergic‐mediated cardiac events were common, occurring in 23 of 27 cases (85%). LQTS was diagnosed in 10 cases (37%), CPVT in 10 (37%) cases, and in 7 cases. No phenotypic diagnosis was provided. Five cases (15%) had evidence for associated skeletal myopathy. Four missense TRDN variants (24%) were observed in diseased cases, while the remaining variants reflect putative loss‐of‐function (LOF) mutations. No disease phenotype was reported in 26 heterozygous carriers. In conclusion, TRDN mutations cause a rare autosomal recessive arrhythmia syndrome presenting with adrenergic‐mediated arrhythmic events, but with ECG abnormalities leading to a diagnosis of LQTS in a proportion of cases. Heterozygous carriers are free of disease manifestations.

Integrative Analyses Identify Potential Key Genes and Calcium-Signaling Pathway in Familial Atrioventricular Nodal Reentrant Tachycardia Using Whole-Exome Sequencing

“…Mouse genome informatics database and previous studies was further used to confirm the phenotype of these genes. The disruption of TRDN contributed to ventricular tachycardia in humans ( Table 2 ; 21 ). Mice lacking ANO6 developed shortened PQ intervals ( Table 2 ).…”

Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

“…Loss-of-function pathogenic variants in the CALM1 , CALM2 , CALM3 and TRDN genes cause LQTS types 14 to 17, respectively. The CALM , CALM2 and CALM3 genes code for calmodulin, and the TRDN gene for triadin, proteins involved in calcium-dependent processes and ion channel regulation [ 43 , 46 ]. LQT14–16 present atypical features, including seizures and neurodevelopmental delay [ 103 ] with symptoms manifesting in infants and young children between the ages of 0–5 years old and a high mortality rate [ 104 ].…”

The Genetics and Epigenetics of Ventricular Arrhythmias in Patients Without Structural Heart Disease

“…Triadn anchors calsequestrin to junctional SR membrane and stabilizes the structure of Ca 2+ release units ( 121 ). TRDN deficiency leads to significantly reduced protein levels of RyR2, calsequestrin, and junctin, impaired coupling efficiency between LTCC and RyR2, reduced SR calcium release and calcium-dependent inactivation of LTCC, resulting in defective cardiac excitation-contraction coupling ( 121 , 122 ). Similarly, Triadin mutations are thought to result in reduced protein levels, which in turnincreased calcium currents and prolonged cardiac action potentials, and increased spontaneous calcium release events caused by cellular and SR calcium overload, which is the basis of TRDN mutation leading to CPVT and LQTS ( 69 , 123 ).…”