TRDN

Inheritance Pattern: AR

Disease ID:MONDO:0014191

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0002442

Submitter: ClinGen

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”

Inheritance Pattern: AR

Disease ID:MONDO:0017990

Submitter: ClinGen

TRDN was evaluated for autosomal recessive catecholaminergic polymorphic ventricular tachycardia (CPVT). TRDN encodes Triadin, a protein important for calcium-release regulation from the sarcoplasmic reticulum. Biallelic loss of function variants in TRDN have been described in CPVT patients in a number of studies (Roux-Buisson et al, 2012, PMID:22422768; Rooryck et al, 2015, PMID:26200674; Walsh et al, 2016, PMID:26768964), including nonsense (p.Gln205Ter, p.Glu168Ter), frameshift (c.53_56del), intronic (c.22+29A>G, with effect on splicing functionally proven) and missense (p.Thr59Arg, the mutant protein was confirmed to be degraded in COS-7 cells and after transfection into knockout mice) variants. An additional report described a homozygous deletion of TRDN exon 2 in an infant who suffered cardiac arrest and subsequent arrhythmia episodes, but this case was scored with only one point due to uncertainty about the phenotype and the additional presence of a RYR2 variant of uncertain significance in this patient (O'Callaghan et al, 2018, PMID:30479949). Biallelic truncating variants in TRDN have also been reported in patients with Long QT syndrome, and the LQTS Gene Curation Expert Panel have previously classified TRDN as having strong evidence for association with LQTS, though with an atypical LQTS phenotype. The variable and atypical phenotypes associated with so-called “Triadin knockout syndrome” should therefore be taken into account when interpreting patients with TRDN biallelic loss of function variants. The association of TRDN with CPVT is also supported by substantial experimental evidence, including expression in heart tissue (Cacheux et al, 2019, PMID:31607542), protein interaction with RYR2 and CASQ2 (Guo et al, 1996, PMID:8550602) and relevant biochemical function in regulating the contractile properties of the heart (Kirchhefer et al, 2001, PMID:11069905). Additionally, knockout mice are directly relevant to the genotypes observed in CPVT patients with TRDN variants, with several studies demonstrating a relevant CPVT phenotype in knockout mice for non-human model organism (e.g. Cacheux et al, 2019, PMID:31607542; Chopra et al, 2009, PMID:19383796) and functional alteration in non-patient cells derived from these mouse knockouts (Chopra et al, 2009, PMID:19383796). Partial rescue of the CPVT phenotype has also been observed in knockout mice treated with AAV2/9 virus encoding rat TRDN isoform Trisk32 (Cacheux et al, 2019, PMID:31607542). In summary, TRDN variants are definitively associated with autosomal recessive CPVT. Note: All CPVT genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the CPVT Gene Curation Expert Panel (GCEP). The classification and summary presented here is the conclusion of this GCEP's analysis according to evidence teams' efforts. This classification was approved by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP Version 7).

Inheritance Pattern: AR

Disease ID:MONDO:0014191

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0014191

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014191

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0019171

Submitter: G2P