Search tips
Search criteria 


Logo of jmedgeneJournal of Medical GeneticsVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
J Med Genet. 2005 December; 42(12): 940–946.
Published online 2005 April 14. doi:  10.1136/jmg.2005.031658
PMCID: PMC1735960

Whole genomewide linkage screen for neural tube defects reveals regions of interest on chromosomes 7 and 10


Neural tube defects (NTDs) are the second most common birth defects (1 in 1000 live births) in the world. Periconceptional maternal folate supplementation reduces NTD risk by 50–70%; however, studies of folate related and other developmental genes in humans have failed to definitively identify a major causal gene for NTD. The aetiology of NTDs remains unknown and both genetic and environmental factors are implicated. We present findings from a microsatellite based screen of 44 multiplex pedigrees ascertained through the NTD Collaborative Group. For the linkage analysis, we defined our phenotype narrowly by considering individuals with a lumbosacral level myelomeningocele as affected, then we expanded the phenotype to include all types of NTDs. Two point parametric analyses were performed using VITESSE and HOMOG. Multipoint parametric and nonparametric analyses were performed using ALLEGRO. Initial results identified chromosomes 7 and 10, both with maximum parametric multipoint lod scores (Mlod) >2.0. Chromosome 7 produced the highest score in the 24 cM interval between D7S3056 and D7S3051 (parametric Mlod 2.45; nonparametric Mlod 1.89). Further investigation demonstrated that results on chromosome 7 were being primarily driven by a single large pedigree (parametric Mlod 2.40). When this family was removed from analysis, chromosome 10 was the most interesting region, with a peak Mlod of 2.25 at D10S1731. Based on mouse human synteny, two candidate genes (Meox2, Twist1) were identified on chromosome 7. A review of public databases revealed three biologically plausible candidates (FGFR2, GFRA1, Pax2) on chromosome 10. The results from this screen provide valuable positional data for prioritisation of candidate gene assessment in future studies of NTDs.

Full Text

The Full Text of this article is available as a PDF (137K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Risch N. Linkage strategies for genetically complex traits. II. The power of affected relative pairs. Am J Hum Genet. 1990 Feb;46(2):229–241. [PubMed]
  • Khoury MJ, Wagener DK. Epidemiological evaluation of the use of genetics to improve the predictive value of disease risk factors. Am J Hum Genet. 1995 Apr;56(4):835–844. [PubMed]
  • Li Hong, Zhao Yixuan, Li Shourou, Xu Yaohong, Huang Bingyu, Cui Manhua, Zheng Guiying. [Epidemiology of twin and twin with birth defects in China]. Zhonghua Yi Xue Za Zhi. 2002 Feb 10;82(3):164–167. [PubMed]
  • Hume RF, Jr, Drugan A, Reichler A, Lampinen J, Martin LS, Johnson MP, Evans MI. Aneuploidy among prenatally detected neural tube defects. Am J Med Genet. 1996 Jan 11;61(2):171–173. [PubMed]
  • Kennedy D, Chitayat D, Winsor EJ, Silver M, Toi A. Prenatally diagnosed neural tube defects: ultrasound, chromosome, and autopsy or postnatal findings in 212 cases. Am J Med Genet. 1998 May 26;77(4):317–321. [PubMed]
  • Toriello HV, Higgins JV. Possible causal heterogeneity in spina bifida cystica. Am J Med Genet. 1985 May;21(1):13–20. [PubMed]
  • Frecker MF, Fraser FC, Heneghan WD. Are 'upper' and 'lower' neural tube defects aetiologically different? J Med Genet. 1988 Jul;25(7):503–504. [PMC free article] [PubMed]
  • Drainer E, May HM, Tolmie JL. Do familial neural tube defects breed true? J Med Genet. 1991 Sep;28(9):605–608. [PMC free article] [PubMed]
  • Garabedian BH, Fraser FC. Upper and lower neural tube defects: an alternate hypothesis. J Med Genet. 1993 Oct;30(10):849–851. [PMC free article] [PubMed]
  • Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, Willett W. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA. 1989 Nov 24;262(20):2847–2852. [PubMed]
  • Chatkupt S, Skurnick JH, Jaggi M, Mitruka K, Koenigsberger MR, Johnson WG. Study of genetics, epidemiology, and vitamin usage in familial spina bifida in the United States in the 1990s. Neurology. 1994 Jan;44(1):65–70. [PubMed]
  • Juriloff DM, Harris MJ. Mouse models for neural tube closure defects. Hum Mol Genet. 2000 Apr 12;9(6):993–1000. [PubMed]
  • Copp Andrew J, Greene Nicholas D E, Murdoch Jennifer N. The genetic basis of mammalian neurulation. Nat Rev Genet. 2003 Oct;4(10):784–793. [PubMed]
  • Harris MJ. Why are the genes that cause risk of human neural tube defects so hard to find? Teratology. 2001 May;63(5):165–166. [PubMed]
  • Melvin EC, George TM, Worley G, Franklin A, Mackey J, Viles K, Shah N, Drake CR, Enterline DS, McLone D, et al. Genetic studies in neural tube defects. NTD Collaborative Group. Pediatr Neurosurg. 2000 Jan;32(1):1–9. [PubMed]
  • O'Connell JR, Weeks DE. PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet. 1998 Jul;63(1):259–266. [PubMed]
  • Epstein MP, Duren WL, Boehnke M. Improved inference of relationship for pairs of individuals. Am J Hum Genet. 2000 Nov;67(5):1219–1231. [PubMed]
  • Boehnke M, Cox NJ. Accurate inference of relationships in sib-pair linkage studies. Am J Hum Genet. 1997 Aug;61(2):423–429. [PubMed]
  • O'Connell JR. Rapid multipoint linkage analysis via inheritance vectors in the Elston-Stewart algorithm. Hum Hered. 2001;51(4):226–240. [PubMed]
  • Ott J. Linkage analysis and family classification under heterogeneity. Ann Hum Genet. 1983 Oct;47(Pt 4):311–320. [PubMed]
  • Boehnke M. Estimating the power of a proposed linkage study: a practical computer simulation approach. Am J Hum Genet. 1986 Oct;39(4):513–527. [PubMed]
  • Ploughman LM, Boehnke M. Estimating the power of a proposed linkage study for a complex genetic trait. Am J Hum Genet. 1989 Apr;44(4):543–551. [PubMed]
  • Gudbjartsson DF, Jonasson K, Frigge ML, Kong A. Allegro, a new computer program for multipoint linkage analysis. Nat Genet. 2000 May;25(1):12–13. [PubMed]
  • Kong Augustine, Gudbjartsson Daniel F, Sainz Jesus, Jonsdottir Gudrun M, Gudjonsson Sigurjon A, Richardsson Bjorgvin, Sigurdardottir Sigrun, Barnard John, Hallbeck Bjorn, Masson Gisli, et al. A high-resolution recombination map of the human genome. Nat Genet. 2002 Jul;31(3):241–247. [PubMed]
  • Matise Tara C, Sachidanandam Ravi, Clark Andrew G, Kruglyak Leonid, Wijsman Ellen, Kakol Jerzy, Buyske Steven, Chui Buena, Cohen Patrick, de Toma Claudia, et al. A 3.9-centimorgan-resolution human single-nucleotide polymorphism linkage map and screening set. Am J Hum Genet. 2003 Aug;73(2):271–284. [PubMed]
  • Broman KW. Estimation of allele frequencies with data on sibships. Genet Epidemiol. 2001 Apr;20(3):307–315. [PubMed]
  • Whittemore AS, Halpern J. A class of tests for linkage using affected pedigree members. Biometrics. 1994 Mar;50(1):118–127. [PubMed]
  • McPeek MS, Strahs A. Assessment of linkage disequilibrium by the decay of haplotype sharing, with application to fine-scale genetic mapping. Am J Hum Genet. 1999 Sep;65(3):858–875. [PubMed]
  • Pericak-Vance MA, Bebout JL, Gaskell PC, Jr, Yamaoka LH, Hung WY, Alberts MJ, Walker AP, Bartlett RJ, Haynes CA, Welsh KA, et al. Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am J Hum Genet. 1991 Jun;48(6):1034–1050. [PubMed]
  • Namjou Bahram, Nath Swapan K, Kilpatrick Jeff, Kelly Jennifer A, Reid Jeff, James Judith A, Harley John B. Stratification of pedigrees multiplex for systemic lupus erythematosus and for self-reported rheumatoid arthritis detects a systemic lupus erythematosus susceptibility gene (SLER1) at 5p15.3. Arthritis Rheum. 2002 Nov;46(11):2937–2945. [PubMed]
  • Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977–1981. [PubMed]
  • Newman B, Austin MA, Lee M, King MC. Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families. Proc Natl Acad Sci U S A. 1988 May;85(9):3044–3048. [PubMed]
  • Angrist M, Kauffman E, Slaugenhaupt SA, Matise TC, Puffenberger EG, Washington SS, Lipson A, Cass DT, Reyna T, Weeks DE, et al. A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10. Nat Genet. 1993 Aug;4(4):351–356. [PubMed]
  • Mankoo Baljinder S, Skuntz Susan, Harrigan Ian, Grigorieva Elena, Candia Al, Wright Christopher V E, Arnheiter Heinz, Pachnis Vassilis. The concerted action of Meox homeobox genes is required upstream of genetic pathways essential for the formation, patterning and differentiation of somites. Development. 2003 Oct;130(19):4655–4664. [PubMed]
  • Walshe J, Mason I. Expression of FGFR1, FGFR2 and FGFR3 during early neural development in the chick embryo. Mech Dev. 2000 Jan;90(1):103–110. [PubMed]
  • Garcès A, Haase G, Airaksinen MS, Livet J, Filippi P, deLapeyrière O. GFRalpha 1 is required for development of distinct subpopulations of motoneuron. J Neurosci. 2000 Jul 1;20(13):4992–5000. [PubMed]
  • Chatkupt S, Hol FA, Shugart YY, Geurds MP, Stenroos ES, Koenigsberger MR, Hamel BC, Johnson WG, Mariman EC. Absence of linkage between familial neural tube defects and PAX3 gene. J Med Genet. 1995 Mar;32(3):200–204. [PMC free article] [PubMed]
  • Hol FA, Geurds MP, Chatkupt S, Shugart YY, Balling R, Schrander-Stumpel CT, Johnson WG, Hamel BC, Mariman EC. PAX genes and human neural tube defects: an amino acid substitution in PAX1 in a patient with spina bifida. J Med Genet. 1996 Aug;33(8):655–660. [PMC free article] [PubMed]
  • Volcik KA, Blanton SH, Kruzel MC, Townsend IT, Tyerman GH, Mier RJ, Northrup H. Testing for genetic associations with the PAX gene family in a spina bifida population. Am J Med Genet. 2002 Jul 1;110(3):195–202. [PubMed]
  • Ramsbottom D, Scott JM, Molloy A, Weir DG, Kirke PN, Mills JL, Gallagher PM, Whitehead AS. Are common mutations of cystathionine beta-synthase involved in the aetiology of neural tube defects? Clin Genet. 1997 Jan;51(1):39–42. [PubMed]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group