Submission Details

CTF-1 was originally evaluated for DCM by the ClinGen DCM GCEP on February 28, 2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on June 14 2024. As a result, the classification changed from limited to no known disease relationship. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. CTF-1 was first reported in relation to autosomal dominant dilated cardiomyopathy in 2000 (Erdmann J et al, PMID: 11058912). Human genetic evidence supporting this gene-disease relationship includes case-level data. At least 7 variants (6 missense and 1 spice site variant) have been reported in humans. Variants in this gene have been reported in at least 10 probands in 3 publications (Erdmann et al, 2000, PMID: 11058912; Pugh et al, 2014, PMID: 24503780; Akinrinade et al, 2015, PMID: 26084686). No segregation data has been reported. This gene-disease relationship has been studied in at least one case-control study at the single variant level (Erdmann et al, 2000, PMID: 11058912), however, this variant was subsequently found to be more commonly expressed in the population than would be expected to explain disease. There is a lack of robust human genetic evidence demonstrating this gene-disease relationship in the literature. No new publications demonstrating CTF-1 variants in DCM were identified during re-curation. Evaluation of the previously identified variants found that all but one of the variants have subsequently been found at a frequency higher than would be expected for a monogenic, pathogenic effect in population reference data sets. This gene-disease association is supported by one animal model (rat) and expression studies (Pennica et al, 1995, PMID: 7862649; Pennica et al, 1996, PMID: 8833032; Zolk et al, 2002, PMID: 12234945; Lopez et al, 2014, PMID: 24366078; Robador et al, 2011, PMID: 21771897; Lopez-Andres et al, 2012, PMID: 22733458). Two additional human expression studies (Sharif et al, 2021, PMID: 34447655; Rubiś et al, 2021, PMID: 34071085) were identified during re-curation. In summary, no convincing evidence for a causal role for CTF-1 and autosomal dominant DCM has been reported. Although this gene-disease assertion is supported by one animal model (rat) and multiple expression studies (human) no reports have directly implicated the gene in humans. Because of this, as well as the lack of new supporting evidence in the four year period since the previous curation, the expert panel has classified this gene as having No Known Disease Relationship for monogenic cause of DCM at this time. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on June 14 2024 (SOP Version 10).