There is currently considerable interest in the relationship between variation in genes that are involved in the folate-homocysteine metabolic axis and the risk of spina bifida. The evaluation of this relationship is, however, complicated by the potential involvement of both the maternal and the embryonic genotype in determination of disease risk. The present study was designed to address questions regarding both maternal and embryonic genetic risk factors for spina bifida by use of the two-step transmission/disequilibrium test. Analysis of data on variants of two genes involved in homocysteine remethylation/methionine biosynthesis--methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G--provided evidence that both variants influence the risk of spina bifida via the maternal rather than the embryonic genotype. For both variants, the risk of having a child with spina bifida appears to increase with the number of high-risk alleles in the maternal genotype: MTR (R1=2.16, 95% CI 0.92-5.06; R2=6.58, 95% CI 0.87-49.67) and MTRR (R1=2.05, 95% CI 1.05-3.99; R2=3.15, 95% CI 0.92-10.85). These findings highlight the importance of considering both the maternal and embryonic genotype when evaluating putative spina bifida susceptibility loci.

Congenital heart disease (CHD), which occurs in about 0.7% of all live-born children, is the leading cause of death from birth defects. Understandably, parents of patients, and increasingly patients themselves, are interested in the risk that further offspring will be affected. Advances in genetics now permit accurate estimation for many forms of CHD, especially the identification of patients and families with recurrence risks of up to 50%. The increased availability of genetic information, combined with the use of noninvasive imaging to look for subtle defects and targeted genetic testing, have demonstrated that the relevant question to ask about an individual's apparently isolated CHD is whether it is syndromic or familial. Syndromes that involve clinically important noncardiac findings may best be managed by, or in consultation with, a clinical geneticist. Other familial syndromes remain entirely within the purview of the cardiologist. The practicing cardiologist needs to continue to stay abreast of genetic discoveries in the field of CHD in order to provide proper management, including genetic counseling, to patients and their families.

The genotype for the NAT1 C1095A polymorphism does not appear to be an independent risk factor for spina bifida. However, the results of these analyses provide preliminary evidence that this polymorphism may be associated with the risk of spina bifida in the offspring of women who smoke during early pregnancy.

The transcription factor T is essential for mesoderm formation and axial development during embryogenesis. Embryonic genotype for a single-nucleotide polymorphism in intron 7 of T ( TIVS7 T/C) has been associated with the risk of spina bifida in some but not all studies. We developed a novel genotyping assay for the TIVS7 polymorphism using heteroduplex generator methodology. This assay was used to genotype spina bifida case-parent trios and the resulting data were analyzed using the transmission disequilibrium test and log-linear analyses. Analyses of these data demonstrated that heterozygous parents transmit the TIVS7-C allele to their offspring with spina bifida significantly more frequently than expected under the assumption of Mendelian inheritance (63 vs 50%, P=0.02). Moreover, these analyses suggest that the TIVS7-C allele acts in a dominant fashion, such that individuals carrying one or more copies of this allele have a 1.6-fold increased risk of spina bifida compared with individuals with zero copies. In silico analysis of the sequence surrounding this polymorphism revealed a potential target site for olfactory neuron-specific factor-1, a transcription factor expressed in the neural tube during development, spanning the polymorphic site. Several other putative, developmentally important and/or environmentally responsive transcription factor-binding sites were also identified close to the TIVS7 polymorphism. The TIVS7 polymorphism or a variant that is in linkage disequilibrium with the TIVS7 polymorphism may, therefore, play a role in T gene expression and influence the risk of spina bifida.

The results of the present analyses suggest that the embryonic NOS3 G894T genotype is associated with the risk of spina bifida. Moreover, these analyses highlight the importance of a detailed examination of the study data. Had these analyses been restricted to the methodologically simpler TDT, the association between the NOS3 G894T genotype and risk of spina bifida may well have been overlooked.