The current study presents two novel GATA6 mutations in patients with nonsyndromic conotruncal heart defects and provides novel insights into the pathogenesis of this disease.
The results indicate that germline mutation of the TGFβ2 gene is not a common cause of CTD in humans and that the TGFβ2 expression level may be less critical in humans than in animals for the pathogenesis of CTD.
Conotruncal defects and atrioventricular septal defects are over-represented in patients with CHD7 mutations compared with patients with nonsyndromic heart defects.
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).
We analyzed the involvement of eight polymorphisms in genes related to folic-acid metabolism, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (MTHFD1), transcobalamin (TCN2), reduced folate carrier (RFC), nicotinamide-N-methyltransferase (NNMT) and natriuretic peptide precursor A (NPPA) as risk factors of conotruncal heart defects.
We analyzed the involvement of eight polymorphisms in genes related to folic-acid metabolism, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (MTHFD1), transcobalamin (TCN2), reduced folate carrier (RFC), nicotinamide-N-methyltransferase (NNMT) and natriuretic peptide precursor A (NPPA) as risk factors of conotruncal heart defects.
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).
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 TYMS 1494del6 (p = 0.048 in the subgroup with classic conotruncal defects).
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.
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.
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).
<b>Conclusion:</b> Our results indicated that SNP rs4705343 in <i>miR-143/145</i> is a potential genetic marker for CTDs in the Chinese Han population.
Our results indicate that the R608W and R616Q variants of TBX2 as well as the A192T and A562V variants of TBX3 contribute to CTD etiology; this was the first association of variants of TBX2 and TBX3 to CTDs based on a large population.
The paternally inherited copy of the GSR (rs7818511) A allele had a 0.31 (95%CI: 0.18, 0.53; p = 9.94 × 10<sup>-6</sup> ] risk of CTHD compared to children with the maternal copy of the same allele.
Our results indicate that the R608W and R616Q variants of TBX2 as well as the A192T and A562V variants of TBX3 contribute to CTD etiology; this was the first association of variants of TBX2 and TBX3 to CTDs based on a large population.
Through biological and in silico analyses, our study suggests an association between SIX1/EYA1 mutations and cardiovascular malformations, SIX1/EYA1 mutations might be partially responsible for CTDs.
Moreover, the MTHFR C677T, MTHFR A1298C, and MTRRA66G polymorphisms were found to be significantly associated with the risk of certain subtypes of CTD.
All these results suggest that CITED2 mutations in conserved regions lead to disease-causing biological and functional changes and may contribute to the occurrence of CTDs.
HIRA (histone cell cycle regulator) gene, as one of the candidate genes located at the critical region of 22q11DS, was reported as possibly relevant to CTD in animal models.
MED13L haploinsufficiency syndrome has been described in two patients and is characterized by moderate intellectual disability (ID), conotruncal heart defects, facial abnormalities and hypotonia.
We found that the spectrum of heart defects depends on Crkl expression, occurring with analogous malformations to that in human individuals, suggesting that haploinsufficiency of CRKL could be responsible for the etiology of CTDs in individuals with nested distal deletions and might act as a genetic modifier of individuals with the typical 3 Mb deletion.