Submission Details

PSEN2 was originally evaluated for DCM by the ClinGen DCM GCEP on December 13, 2019. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on October 4, 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. PSEN2 was first reported in relation to autosomal dominant dilated cardiomyopathy in 2006 (Li et al. PMID: 17186461). Human genetic evidence supporting this gene-disease relationship includes case level data. Two missense variants have been reported in 4 probands in two studies (Li et al. PMID: 17186461, Gianni et al. PMID: 20194882). While Li et al. demonstrated limited segregation and functional evidence for the missense variant identified in their study, both of the reported missense variants have subsequently been found at a frequency higher than would be expected for a monogenic, pathogenic effect in population reference data sets. No new human genetic evidence has emerged since the last curation. This gene-disease relationship is supported by expression studies (Mohuczy et al. PMID: 12468103, Gupta et al. PMID: 20443895). No new experimental evidence was identified in this re-curation. In summary, no convincing evidence for a causal role for PSEN2 and autosomal dominant DCM has been reported. Because of this, as well as the lack of new supporting evidence in the 4 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 May 30th, 2025 (SOP Version 10).