TRDN encodes Triadin, a protein important for calcium-release regulation from the sarcoplasmic reticulum. Evidence for involvement of TRDN in LQTS is based mainly on a single publication using exome sequencing to investigate a genotype-negative LQTS case with clinical findings concordant with autosomal recessive or sporadic inheritance (PMID 25922419). Following identification of homozygous frameshift variant in TRDN, 4 other patients with homozygous or compound heterozygous frameshift variants in TRDN were identified in a cohort of 33 unrelated genotype-negative LQTS patients. All cases presented during early childhood (up to the age of 3 years) with QT prolongation, negative T waves in precordial leads (figure 2) and exercise-induced arrhythmias, although typical torsades de pointes (TdP) was demonstrated only in one case. Experimental evidence demonstrated that TRDN loss of function may lead to arrhythmogenesis but did not specifically show prolongation of repolarization which is the hallmark of LQTS. Accordingly, there was a debate within the panel as to whether the TRDN-related cardiac phenotype should be classified as catecholaminergic polymorphic ventricular tachycardia or as a unique syndrome, referred in the literature as triadin knockout syndrome (TKOS) (PMID 26200674). Because QT prolongation was the most easily discernable abnormality it was decided to consider these cases as having an atypical LQTS phenotype. Furthermore, it was agreed that there was strong evidence for TRDN’s disease association. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the LQTS Clinical Domain Working Group. The classification and summary presented here is the conclusion of this Working Group's analysis according to evidence teams' efforts. For a detailed discussion of this group's work and the scores of all 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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