Submission Details

CRELD1 was first reported in relation to autosomal dominant Congenital heart disease in 2003 (Robinson et al., PMID: 12632326).* CRELD1* has been noted to be associated with the following disease entities: Atrioventricular septal defect (AVSD), susceptibility to 2; AVSD, partial, with heterotaxy syndrome; AVSD, Down syndrome-associated; congenital heart defect (CHD); tetralogy of Fallot (TOF); and left ventricular noncompaction (LVNC). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability of AVSD, AVSD with heterotaxy syndrome, CHD, and TOF. Therefore, these disease entities have been lumped into one disease entity. The split curation for AVSD, Down syndrome- associated will be curated separately. A missense variant that has been reported in a proband is included in this curation (PMID: 22740159). At least 21 other unique variants (missense, frameshift, splice site) have been reported in 46 probands in 11 publications (PMIDs: 12632326, 15857420, 18076106, 24927998, 22740159, 29054759, 34328347, 21413875, 21080147, 28798025, 36011280). However, these variants were not included in the curation due to either a high minor allele frequency (> 0.00001) in gnomAD v.2.1.1 or a low REVEL score (< 0.7). CRELD1 variants are incompletely penetrant and require interactions with other risk factors to increase the risk of developing a heart defect. This gene-disease association is also supported by three knockout mouse models that show that Creld1 is important for VEGF signaling and heart development (PMIDs: 25328912, 24697899, 33773999). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 9/5/2023 (SOP Version 9).