TRDN – Triadin-associated Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal inherited arrhythmia marked by adrenergic-triggered bidirectional or polymorphic ventricular tachycardia. While 50% of CPVT cases are due to dominant RYR2 variants, recessive TRDN mutations account for <5% of cases and define triadin knockout syndrome (PMID:29178653).

Genetic studies have identified 27 affected individuals from 21 unrelated families with autosomal recessive TRDN variants, including homozygous splice-site mutations (c.22+1G>T) and nonsense/missense alleles, establishing a consistent loss-of-function spectrum (PMID:34415104). Founder analysis in an Iranian cohort revealed c.22+1G>T in multiple probands. Variant classes include splice-site, frameshift, and missense mutations; no phenotype is observed in heterozygous carriers.

Segregation analyses in multiple families demonstrate cosegregation of biallelic TRDN variants with CPVT, with at least two pedigrees showing concordant affected siblings (PMID:22422768). A recurrent homozygous splice-site variant (c.22+1G>T) supports a founder effect in specific populations.

Functional assays in heterologous cells and triadin-null animal models confirm that TRDN loss abrogates triadin expression, disrupts the cardiac calcium release complex, and precipitates arrhythmia. Induced pluripotent stem cell-derived cardiomyocytes from TRDN-deficient patients exhibit prolonged action potentials and calcium handling defects, reversible by triadin replacement (PMID:37163978).

Integrated evidence meets ClinGen criteria for a Strong gene-disease validity classification: robust genetic data with numerous unrelated probands, segregation, and concordant functional studies. Key pathogenic mechanism is loss-of-function leading to defective excitation–contraction coupling. Additional deep-intronic and founder variants remain to be explored.

Key Take-home: TRDN should be included in autosomal recessive CPVT genetic testing panels to guide diagnosis, risk stratification, and family counseling.

References

• Molecular Genetics & Genomic Medicine • 2017 • Compound heterozygous CASQ2 mutations and long-term course of catecholaminergic polymorphic ventricular tachycardia PMID:29178653
• 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
• 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
• Stem Cell Reports • 2023 • Cellular and electrophysiological characterization of triadin knockout syndrome using induced pluripotent stem cell-derived cardiomyocytes PMID:37163978

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