How to Cite this Article: Browne ML, Carter TC, Kay DM, Kuehn D, Brody LC, Romitti PA, Liu A, Caggana M, Druschel CM, Mills JL. 2012. Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies. Am J Med Genet Part A 158A: 2463–2472.
Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies†
Version of Record online: 10 SEP 2012
Copyright © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 158A, Issue 10, pages 2463–2472, October 2012
How to Cite
Browne, M. L., Carter, T. C., Kay, D. M., Kuehn, D., Brody, L. C., Romitti, P. A., Liu, A., Caggana, M., Druschel, C. M. and Mills, J. L. (2012), Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies. Am. J. Med. Genet., 158A: 2463–2472. doi: 10.1002/ajmg.a.35565
- Issue online: 18 SEP 2012
- Version of Record online: 10 SEP 2012
- Manuscript Accepted: 20 JUN 2012
- Manuscript Received: 26 APR 2012
- Intramural Research Program of the National Institutes of Health. Grant Number: HHSN267200703431C
- Eunice Kennedy Shriver National Institute of Child Health and Human Development NICHD. Grant Number: N01-DK-7-3431
- National Human Genome Research Institute
- limb deficiencies;
We conducted a population-based case–control study of single nucleotide polymorphisms (SNPs) in selected genes to find common variants that play a role in the etiology of limb deficiencies (LDs). Included in the study were 389 infants with LDs of unknown cause and 980 unaffected controls selected from all births in New York State (NYS) for the years 1998–2005. We used cases identified from the NYS Department of Health (DOH) Congenital Malformations Registry. Genotypes were obtained for 132 SNPs in genes involved in limb development (SHH, WNT7A, FGF4, FGF8, FGF10, TBX3, TBX5, SALL4, GREM1, GDF5, CTNNB1, EN1, CYP26A1, CYP26B1), angiogenesis (VEGFA, HIF1A, NOS3), and coagulation (F2, F5, MTHFR). Genotype call rates were >97% and SNPs were tested for departure from Hardy–Weinberg expectations by race/ethnic subgroups. For each SNP, odds ratios (OR)s and confidence intervals (CI)s were estimated and corrected for multiple comparisons for all LDs combined and for LD subtypes. Among non-Hispanic white infants, associations between FGF10 SNPs rs10805683 and rs13170645 and all LDs combined were statistically significant following correction for multiple testing (OR = 1.99; 95% CI = 1.43–2.77; uncorrected P = 0.000043 for rs10805683 heterozygous genotype, and OR = 2.37; 95% CI = 1.48–3.78; uncorrected P = 0.00032 for rs13170645 homozygous minor genotype). We also observed suggestive evidence for associations with SNPs in other genes including CYP26B1 and WNT7A. Animal studies have shown that FGF10 induces formation of the apical ectodermal ridge and is necessary for limb development. Our data suggest that common variants in FGF10 increase the risk for a wide range of non-syndromic limb deficiencies. © 2012 Wiley Periodicals, Inc.