TRDN – Long QT Syndrome

Triadin, encoded by TRDN, is a sarcoplasmic reticulum protein that anchors the ryanodine receptor–calsequestrin complex in cardiomyocytes. Autosomal recessive variants in TRDN cause a malignant arrhythmia syndrome featuring catecholaminergic polymorphic ventricular tachycardia (CPVT) and, in a subset of patients, resting prolonged QT intervals diagnostic of Long QT syndrome. This overlap leads to clinical misdiagnosis and underscores the need for comprehensive genetic testing and interpretation.

Genetic evidence derives from 27 affected individuals across 21 unrelated families (all biallelic) with mean age of onset 30 months. Resting LQTS was documented in 10 of 27 cases, and adrenergic‐mediated events occurred in 23 of 27 patients (PMID:34415104). No disease was observed in 26 heterozygous carriers, confirming autosomal recessive inheritance and full penetrance in homozygotes.

The variant spectrum includes predominantly loss-of-function alleles (splice-site, nonsense, frameshift) and four missense changes. A presumptive founder splice mutation, c.22+1G>T, was homozygous in two unrelated Iranian children presenting with resting QT prolongation and exercise‐induced CPVT (PMID:34415104). A recently characterized missense variant, c.167T>C (p.Leu56Pro), disrupts triadin dynamics and reduces caffeine‐induced calcium release when coexpressed with RyR2 (PMID:31437535).

Functional studies across model systems establish triadin haploinsufficiency as the mechanism of pathogenicity. Triadin-null mice and iPSC-derived cardiomyocytes exhibit prolonged action potential duration, reduced SR calcium release, and frequent afterdepolarizations, all reversible by triadin replacement (PMID:37163978). COS-7 expression assays of p.Thr59Arg and p.Thr59Met mutants demonstrate intracellular retention and degradation, consistent with loss of function (PMID:22422768).

An international reappraisal of congenital LQTS genes classified TRDN among four genes with strong or definitive evidence for causality in LQTS with atypical features, supporting its inclusion in diagnostic panels (PMID:31983240).

Integration of genetic and functional data fulfills ClinGen criteria for a Strong gene–disease association. TRDN variant analysis is thus critical for accurate diagnosis of pediatric LQTS and related arrhythmias and informs family counseling and management.

Key Take-home: Biallelic TRDN loss-of-function and select missense variants cause an autosomal recessive LQTS phenotype with adrenergic arrhythmias, warranting inclusion of TRDN in LQTS genetic testing panels.

References

• American journal of medical genetics. Part A • 2021 • 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. PMID:34415104
• Heart rhythm • 2020 • A novel homozygous mutation in the TRDN gene causes a severe form of pediatric malignant ventricular arrhythmia. PMID:31437535
• Stem cell reports • 2023 • Cellular and electrophysiological characterization of triadin knockout syndrome using induced pluripotent stem cell-derived cardiomyocytes. PMID:37163978
• Circulation • 2020 • An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. PMID:31983240
• Human molecular genetics • 2012 • Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human. PMID:22422768

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