Robinson et al. (2003) analyzed a group of subjects with partial AVSD for mutations in the CRELD1 gene, which maps to chromosome 3p25 and is expressed in the developing heart. They identified heterozygous mutations in the CRELD1 gene ... Robinson et al. (2003) analyzed a group of subjects with partial AVSD for mutations in the CRELD1 gene, which maps to chromosome 3p25 and is expressed in the developing heart. They identified heterozygous mutations in the CRELD1 gene in 3 of 50 patients, including mutations in isolated AVSD (607170.0001-607170.0002) and AVSD associated with heterotaxy syndrome (607170.0003). Among 49 patients with AVSD, Zatyka et al. (2005) identified 5 novel sequence variants in the CRELD1 gene. Three of the novel variants were also identified in normal controls, 1 was a silent change, and 1 was also seen in 2 family members without congenital heart disease (607170.0004). Genetic analysis of 12 patients with 3p- syndrome showed that the CRELD1 gene was deleted in all 5 patients with an AVSD but was also deleted in 4 patients without congenital heart disease. Zatyka et al. (2005) concluded that CRELD1 deletions are unlikely to account for AVSD in children with 3p deletions but that rare missense mutations may confer susceptibility to AVSD in a subset of patients. Ackerman et al. (2012) confirmed the role of CRELD1 in AVSD in a study of 141 individuals with Down syndrome and complete AVSD (cases) and 141 individuals with Down syndrome and no congenital heart defect (controls) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. Ackerman et al. (2012) found a significant excess (p less than 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, they found potentially damaging variants in nearly 20% of cases but in fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in 6 genes: COL6A1 (120220), COL6A2 (120240), CRELD1, FBLN2 (135821), FRZB (605083), and GATA5 (611496). Of note, all of these genes are in the VEGFA (192240) pathway, suggesting to Ackerman et al. (2012) that rare variants in this pathway might contribute to the genetic underpinnings of AVSD in humans.