Submission Details

DAND5 was first reported in relation to autosomal dominant congenital heart disease in 2017 (Cristo et al., PMID: 28738792). Two heterozygous missense variants have been reported in two probands in two publications (PMID: 28738792, 28230599) are included in this curation. However, these variants were not scored as they are too frequent and one was reported in a proband with a different causal variant identified (PMID 28230599). Two homozygous genotypes were also reported, but those variants were identified in the context of long regions of homozygosity that could contain causal variants (PMID 34215651, 36316122). This gene-disease relationship is supported by animal models and expression studies. Expression studies confirmed that DAND5 is expressed early in zebrafish and amphioxus development (PMIDs 15084459, 31826864). Many zebrafish models with abnormal heart looping also demonstrate alterations in dand5 expression, most frequently at the left-right organizer (PMIDs 15084459, 22535411, 26493400, 34903892, 38307837). Zebrafish models demonstrated that deficiency of dand5 led to abnormal cardiac looping (PMIDs 15084459, 30446628). Mouse embryonic cell lines deficient for Dand5 had increased mesoderm differentiation and increased beating foci (PMID 33928078). A zebrafish model demonstrated rescue of a cardiac looping phenotype with morpholino depletion of dand5 after overexpression (PMID 15084459). In summary, the evidence supporting the relationship between DAND5 and congenital heart disease with unknown mode of inheritance has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role DAND5 plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date June 4, 2024 (SOP Version 10).