The genetic basis of cardiac septal defects

Mutations in single genes are reported in a minority of non-syndromic CSD and CRELD1, a candidate gene for atrioventricular septal defect (AVSD), is described. Periconceptional folic acid supplements may reduce the risk of CHD, particularly VSD. The enzyme, 5,10-methylenetetrahydrofolate reductase (MTHFR) is important in nucleotide synthesis, DNA and protein methylation and the conversion of homocysteine to methionine. Reduced MTHFR activity in those homozygous for the C677T and A1298C variants of the MTHFR gene and compound heterozygotes, has been observed and C677T homozygosity in the mother and index child is associated with increased risk of neural tube defects. The primary aim was to study the role of genetic variation in MTHFR, in ventricular and AVSD using a case/parent triad design. Secondary aims were to assess any gene-environment interaction with maternal dietary folate and supplemented folic acid intake and to assess the role of CRELD1 in individuals with AVSD. 194 case-parent triads were recruited. No association of MTHFR C677T variant alleles in infants or mothers with VSD risk was observed. A reduced relative risk in mothers with one or two MTHFR A1298C variant alleles, RR 0.66 (95%CI 0.44-0.98, p=0.04) was observed. No significant interaction of genotype and folic acid supplements or dietary folate was demonstrated. 38 AVSD case-parent triads were recruited, 15 of the affected AVSD cases were sequenced for CRELD1. Two sequence variants (G37A, G945A) were identified in CRELD1 in five Scottish samples. G37A, is a polymorphism associated with AVSD and G945A is a novel variant, predicted to be a synonymous change but may alter splicing of the protein. 3.6%, of 110 Scottish controls were heterozygous for G945A, confirming it is a polymorphism.EThOS - Electronic Theses Online ServiceGBUnited Kingdo