Provide your Rationale: (Evidence summary paragraph as written in GCI) TBX20 was originally evaluated for DCM by the ClinGen DCM GCEP on 8/12/20. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 2/5/2025. As a result, the classification did change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein.
TBX20 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2007 (Kirk et al, PMID: 17668378. Human genetic evidence supporting the gene-disease relationship with DCM includes case-level, case-control and segregation data. Multiple unique variants (missense and truncating) in TBX20 have been reported in individuals with DCM, Left Ventricular Non-Compaction (LNVC), Congenatal Heart Disease and/or Wolff-Parkinson-White Syndrome (Kirk et al, 2007, PMID: 17668378; Qian et al, 2008 PMID: 19074289; Amor-Salamanca et al 2024 PMID: 38353104; Chang et al 2024 PMID: 37657916), 6 of which were scored as variant evidence for this curation. One case-control study using aggregate variant analysis found that TBX20 truncating variants were enriched in probands with DCM/LVNC compared to internal and external control groups, with an odds ratio of 73.23 (p<0.0001; Amor-Salamanca et al 2024, PMID: 38353104). Segregation evidence from two studies, using candidate gene or genome-wide sequencing, showed that TBX20 truncating variants segregated with DCM/LNVC phenotypes, with a combined LOD score of 5.73 (Amor-Salamanca et al 2024 PMID: 38353104; Chang et al 2024 PMID: 37657916). Additional publications that presented genetic evidence were excluded due to concerns of suspect data (Zhao et al, 2016, PMID: 26118961; Zhou et al, 2016, PMID:27510170). In addition, this gene-disease association is supported by animal models and expression studies. The mechanism of disease is unclear at this time as TBX20 loss-of-function and gain-of-function (overexpression) animal models have produced similar phenotypes (Stennard et al, 2005,PMID: 15843414, Zhang et al, 2011, PMID: 21890625). In summary, TBX20 is strongly associated with AD DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on May 2nd, 2025 (SOP Version 10).
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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