Analyses that investigated a potential gene-nutrient interaction between maternal periconceptional vitamin use and MTHFR genotypes did not indicate that the CT or TT genotype contributed to conotruncal defect risk in infants even in the absence of maternal use of multivitamin supplements with folic acid.
Methylenetetrahydrofolate reductaseC677T and reduced folate carrier 80 G>A polymorphisms are associated with an increased risk of conotruncal heart defects.
Moreover, the MTHFR C677T, MTHFRA1298C, and MTRR A66G polymorphisms were found to be significantly associated with the risk of certain subtypes of CTD.
The A1298CMethylenetetrahydrofolate Reductase Gene Variant as a Susceptibility Gene for Non-Syndromic Conotruncal Heart Defects in an Indian Population.
The risk of CTHD among children who inherited a paternally derived copy of the A allele on GLRX (rs17085159) or the T allele of GLRX (rs12109442) was 0.23 (95%CI: 0.12, 0.42; p = 1.09 × 10<sup>-6</sup> ) and 0.27 (95%CI: 0.14, 0.50; p = 2.06 × 10<sup>-5</sup> ) times the risk among children who inherited a maternal copy of the same allele.
Given that patients with septal and conotruncal defect can share a common genetic basis, it is unclear whether patients with additional types of CHD might also have GATA4 mutations.
The A allele of MTHFD1rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR = 1.7, 95% CI = 1.1-2.5) and Hispanic infants (OR = 1.7, 95% CI = 1.2-2.3).
The syndrome is characterized by a broad phenotype, whose characterization has expanded considerably within the last decade and includes many associated findings such as craniofacial anomalies (40%), conotruncal defects of the heart (CHD; 70-80%), hypocalcemia (20-60%), and a range of neurocognitive anomalies with high risk of schizophrenia, all with a broad phenotypic variability.
One SNP pair (i.e., rs4764267 and rs6556883) located in gene MGST1 and GLRX, respectively, was found to be associated with CTD risk after multiple testing adjustment using simpleM, a modified Bonferroni correction approach (nominal p-value of 4.62e-06; adjusted p-value of .04).
However, our results suggest that CTRD risk may be associated with the maternal genotype for NOS3 894G>T (p = 0.024 in the subgroup with normally related great arteries) and TYMS1494del6 (p = 0.048 in the subgroup with classic conotruncal defects).
Analyses that investigated a potential interaction on risk between NOS3 genes and maternal cigarette smoking, revealed some evidence for higher risk of conotruncal defects in infants whose mothers smoked cigarettes periconceptionally and who had one of the variant alleles for NOS3 A(-922G) or NOS3glu298asp compared to those infants whose mothers did not smoke and whose genotypes were wild-type.
We evaluated five single-nucleotide polymorphisms (SNPs) in genes related to folic acid metabolism: methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), solute carrier family 19, member 1 (SLC19A1 G80A), methionine synthase (MTRA2576G), and methionine synthase reductase (MTRR A66G), as risk factors for CTDs including various types of malformation, in a total of 193 mothers with CTD-affected offspring and 234 healthy controls in a Chinese population.
We conclude that CHD7 mutations are not a major cause of the atrioventricular septal defects and conotruncal heart defects, not even if one extra phenotypic feature of CHARGE syndrome is present.