DNA has been obtained from approximately 20 major malformations for current and future investigations. In addition, cases have been selected for copy number variant studies and the first samples have been analyzed by large scale copy number variant array testing. The initial phase of data cleaning, editing and analysis is beginning. Samples have been tested in cases and controls in collaboration with consortia performing genome wide association studies. We are providing subjects for confirmatory genotyping in several studies. Our first publications on Hirshcsprung's disease and omphalocele have recently appeared in print. Hirschsprung's disease (HSCR) results from failed colonization of the embryonic gut by enteric neural crest cells (ENCCs);colonization requires RET proto-oncogene (RET) signaling. We sequenced RET to identify coding and splice-site variants in a population-based case group and we tested for associations between HSCR and common variants in RET and candidate genes (ASCL1, homeobox B5 (HOXB5), L1 cell adhesion molecule (L1CAM), paired-like homeobox 2b (PHOX2B), PROK1 and PROKR1) chosen because they are involved in ENCC proliferation, migration and differentiation in animal models. We conducted a nested case-control study of 304 HSCR cases and 1215 controls. Among 38 (12.5%) cases with 34 RET coding and splice-site variants, 18 variants were previously unreported. We confirmed associations with common variants in HOXB5 and PHOX2B but the associations with variants in ASCL1, L1CAM and PROK1 were not significant after multiple comparisons adjustment. RET variants were strongly associated with HSCR (P-values between 10(-3) and 10(-31)) but this differed by race/ethnicity: associations were absent in African-Americans. Our population-based study not only identified novel RET variants in HSCR cases, it showed that common RET variants may not contribute to HSCR in all race/ethnic groups. The findings for HOXB5 and PHOX2B provide supportive evidence that genes regulating ENCC proliferation, migration and differentiation could be risk factors for HSCR. Both taking folic acid-containing vitamins around conception and consuming food fortified with folic acid have been reported to reduce omphalocele rates. Genetic factors are etiologically important in omphalocele as well;our pilot study showed a relationship with the folate metabolic enzyme gene methylenetetrahydrofolate reductase (MTHFR). We studied 169 non-aneuploid omphalocele cases and 761 unaffected, matched controls from all New York State births occurring between 1998 and 2005 to look for associations with single nucleotide polymorphisms (SNPs) known to be important in folate, vitamin B12, or choline metabolism. In the total study population, variants in the transcobalamin receptor gene (TCblR), rs2232775 (p.Q8R), and the MTHFR gene, rs1801131 (c.1298A>C), were significantly associated with omphalocele. In African-Americans, significant associations were found with SNPs in genes for the vitamin B12 transporter (TCN2) and the vitamin B12 receptor (TCblR). A SNP in the homocysteine-related gene, betaine-homocysteine S-methyltransferase (BHMT), rs3733890 (p.R239Q), was significantly associated with omphalocele in both African-Americans and Asians. Only the TCblR association in the total population remained statistically significant if Bonferroni correction was applied. The finding that transcobalamin receptor (TCblR) and transporter (TCN2) SNPs and a BHMT SNP were associated with omphalocele suggests that disruption of methylation reactions, in which folate, vitamin B12, and homocysteine play critical parts, may be a risk factor for omphalocele. Our data, if confirmed, suggest that supplements containing both folic acid and vitamin B12 may be beneficial in preventing omphaloceles. Work is ongoing on several other case control studies looking at candidate genes for association with major birth defects.

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Dimopoulos, Aggeliki; Sicko, Robert J; Kay, Denise M et al. (2017) Rare copy number variants in a population-based investigation of hypoplastic right heart syndrome. Birth Defects Res 109:8-15
Dimopoulos, Aggeliki; Sicko, Robert J; Kay, Denise M et al. (2017) Copy number variants in a population-based investigation of Klippel-Trenaunay syndrome. Am J Med Genet A 173:352-359
Hagen, Erin M; Sicko, Robert J; Kay, Denise M et al. (2016) Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways. Hum Genet 135:1355-1364
Mills, James L; Dimopoulos, Aggeliki; Bailey, Regan L (2016) What is standing in the way of complete prevention of folate preventable neural tube defects? Birth Defects Res A Clin Mol Teratol 106:517-9
Boghossian, Nansi S; Sicko, Robert J; Kay, Denise M et al. (2016) Rare copy number variants implicated in posterior urethral valves. Am J Med Genet A 170:622-33
Wang, Yifan; Liu, Aiyi; Mills, James L et al. (2015) Pleiotropy analysis of quantitative traits at gene level by multivariate functional linear models. Genet Epidemiol 39:259-75
Mills, James L (2015) Preventing folate-related neural tube defects: Problem solved, or not? Birth Defects Res A Clin Mol Teratol 103:469-70
Bailey, Lynn B; Stover, Patrick J; McNulty, Helene et al. (2015) Biomarkers of Nutrition for Development-Folate Review. J Nutr 145:1636S-1680S
Rigler, Shannon L; Kay, Denise M; Sicko, Robert J et al. (2015) Novel copy-number variants in a population-based investigation of classic heterotaxy. Genet Med 17:348-57
Fan, Ruzong; Wang, Yifan; Mills, James L et al. (2014) Generalized functional linear models for gene-based case-control association studies. Genet Epidemiol 38:622-637

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