Atrioventricular Septal Defect, Susceptibility To, 2

A number sign (#) is used with this entry because susceptibility to atrioventricular septal defect-2 (AVSD2) is conferred by heterozygous mutation in the gene encoding cell adhesion molecule CRELD1 (607170) on chromosome 3p25.

For a phenotypic description and a discussion of genetic heterogeneity of AVSD, see 606215.

Mapping

Green et al. (2000) studied 10 individuals with chromosome 3pter-p25 deletions (613792), 5 of whom had congenital heart disease. Congenital heart defects, typically AVSD, occur in approximately one-third of individuals with 3p- syndrome (Phipps et al., 1994; Drumheller et al., 1996). Green et al. (2000) identified a susceptibility locus for AVSD in cytogenetic band 3p25, bounded by markers at D3S1263 and D3S3594, an interval of 3.7 cM.

Kozma et al. (2004) studied a family segregating a balanced t(1;3)(q42.3;p25) translocation that led to 2 types of viable unbalanced complements: derivative chromosome 3, resulting in partial trisomy of 1q and partial monosomy of 3p, and derivative chromosome 1, resulting in partial monosomy for 1q and partial trisomy for 3p. The authors noted that both rearrangements led to profound mental and physical retardation and congenital heart defects, but each had a distinct facial dysmorphism. Two patients with derivative chromosome 3 had large AVSDs.

Molecular Genetics

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.