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EB Research - Pediatric Epidemiology

Genetic Factors in Birth Defects Study

The Genetic Factors in Birth Defects Study is a multicenter, multidisciplinary study led by NICHD to identify genetic risk factors for a wide range of major birth defects. The collaborating institutions are NICHD, The National Human Genome Research Institute, The New York State Department of Health, and The University of Iowa. The New York State Congenital Malformations Registry has identified approximately 13,000 children who have major birth defects and suitable unaffected controls from among all New York births. This information has been linked to blood spots retained after testing in the newborn period. DNA has been extracted and has been used to test for genetic variants associated with these birth defects.

A variety of defects has been selected and analyzed using a candidate gene approach. To date genetic variants (single nucleotide polymorphisms) have been identified and the results reported in the literature for:

  • Omphalocele
  • Hirschsprung’s disease
  • Limb defects
  • Ano-rectal atresia

Additional defects are currently being examined. Because of the very large number of affected children included in this study, it has been possible to examine relatively rare conditions such as non-syndromic omphalocele.

The large number of cases has also enabled the group to make substantial contributions to consortia performing genome wide association studies. The group is currently collaborating in one such study examining craniosynostosis and another examining pyloric stenosis. The group is interested in exploring collaborations with investigators conducting such studies.

The group has recently demonstrated the feasibility of conducting genome wide studies of copy number variants using DNA obtained from blood spots. This has opened a whole new area of investigation. Because of the very large number of subjects available for study, the group has sufficient numbers to look for copy number variants associated with rare defects. Many such birth defects are now being tested for the presence of copy number variants.

Principal Investigator

James Mills, M.D., M.S.

DIPHR Collaborators

Extramural Collaborators

  • Denise Kay, Ph.D., New York State Health Dept.
  • Michele Caggana, Ph.D., New York State Health Dept.
  • Marilyn Browne, Ph.D., New York State Health Dept. and State University N.Y. Albany
  • Charlotte Druschel, M.D., New York State Health Dept. and State University N.Y. Albany
  • Lawrence Brody, Ph.D. NHGRI, NIH
  • Mills JL, Troendle J, Conley MR, Carter T, Druschel CM. Maternal obesity and congenital heart defects: a population-based study. Am J Clin Nutr. 2010 Jun;91(6):1543-9. PMID:20375192

Selected Publications

  • Carter TC, Kay DM, Browne ML, Liu A, Romitti PA, Kuehn D, Conley MR, Caggana M, Druschel CM, Brody LC, Mills JL. Anorectal atresia and variants at predicted regulatory sites in candidate genes. Ann Hum Genet. 2013;77:31-46. PMID:23127126
  • Mills JL, Carter TC, Kay DM, Browne M, Brody LC, Liu A, Romitti PA, Caggana M, Druschel C. Folate and vitamin B12 related genes and risk for omphalocele. Hum Genet. 2012;131:739-46. PMID:22116453
  • Carter TC, Kay DM, Browne ML, Liu A, Romitti PA, Kuehn D, Conley MR, Caggana M, Druschel CM, Brody LC, Mills JL. Hirschsprung’s disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation. J Hum Genet. 2012; 57:485-93. PMID:22648184
  • Browne ML, Carter TC, Kay DM, Kuehn D, Brody LC, Romitti PA, Liu A, Caggana M, Druschel CM, Mills JL. Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies. Am J Med Genet A. 2012. 158A:2463-72. PMID:22965740
  • Justice CM, Yagnik G, Kim Y, Peter I, Jabs EW, Erazo M, Ye X, Ainehsazan E, Shi L, Cunningham ML, Kimonis V, Roscioli T, Wall SA, Wilkie AO, Stoler J, Richtsmeier JT, Heuzé Y, Sanchez-Lara PA, Buckley MF, Druschel CM, Mills JL, Caggana M, Romitti PA, Kay DM, Senders C, Taub PJ, Klein OD, Boggan J, Zwienenberg-Lee M, Naydenov C, Kim J, Wilson AF, Boyadjiev SA. A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat Genet. 2012;44:1360-4. PMID:23160099
  • Beaty TH, Murray JC, Marazita ML, Munger RG, Ruczinski I, Hetmanski JB, Liang KY, Wu T, Murray T, Fallin MD, Redett RA, Raymond G, Schwender H, Jin SC, Cooper ME, Dunnwald M, Mansilla MA, Leslie E, Bullard S, Lidral AC, Moreno LM, Menezes R, Vieira AR, Petrin A, Wilcox AJ, Lie RT, Jabs EW, Wu-Chou YH, Chen PK, Wang H, Ye X, Huang S, Yeow V, Chong SS, Jee SH, Shi B, Christensen K, Melbye M, Doheny KF, Pugh EW, Ling H, Castilla EE, Czeizel AE, Ma L, Field LL, Brody L, Pangilinan F, Mills JL, Molloy AM, Kirke PN, Scott JM, Arcos-Burgos M, Scott AF. A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet. 2010. 42:525-9. PMID:20436469

Contact Information

Name: Dr Enrique Fabian Schisterman
Chief and Senior Investigator
Epidemiology Branch
Phone: 301-435-6893
Fax: 301-402-2084

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