Rare variants in BMP4, CRELD1, CRELD2, FBLN2, FRZB, GATA4 and GATA5 genes have been found in individuals with DS and complete AVSD, suggesting that rare genetic variants in these genes, incompletely penetrant on an euploid background, may act synergistically with T21 to increase the risk for AVSD in DS [59,60,61,62]. The gene discussed is CRELD2; the disease is familial atrioventricular septal defect.