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Original article
Whole genomewide linkage screen for neural tube defects reveals regions of interest on chromosomes 7 and 10
  1. E Rampersaud1,
  2. A G Bassuk2,
  3. D S Enterline1,
  4. T M George1,
  5. D G Siegel1,
  6. E C Melvin1,
  7. J Aben3,
  8. J Allen1,
  9. A Aylsworth4,
  10. T Brei5,
  11. J Bodurtha6,
  12. C Buran5,
  13. L E Floyd1,
  14. P Hammock1,
  15. B Iskandar7,
  16. J Ito8,
  17. J A Kessler2,
  18. N Lasarsky9,
  19. P Mack9,
  20. J Mackey1,
  21. D McLone8,
  22. E Meeropol9,
  23. L Mehltretter1,
  24. L E Mitchell10,
  25. W J Oakes11,
  26. J S Nye12,
  27. C Powell3,
  28. K Sawin5,
  29. R Stevenson13,
  30. M Walker14,
  31. S G West1,
  32. G Worley1,
  33. J R Gilbert1,
  34. M C Speer1
  1. 1Duke University Medical Center, Durham, NC, USA
  2. 2Northwestern University’s Feinberg School of Medicine, Departments of Pediatrics and Neurology and Children’s Memorial Hospital, Chicago, IL, USA
  3. 3Children’s Rehabilitation Service, Birmingham, AL, USA
  4. 4University of North Carolina, Chapel Hill, NC, USA
  5. 5Indiana University School of Medicine, Indianapolis, IN, USA
  6. 6Virginia Commonwealth University, Richmond, VA, USA
  7. 7University of Wisconsin Hospitals, Madison, WI, USA
  8. 8Children’s Memorial Hospital, Chicago, IL, USA
  9. 9Shriner’s Hospital, Springfield, IL, USA
  10. 10Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA
  11. 11University of Alabama, Birmingham, USA
  12. 12Johnson & Johnson, Princeton, USA
  13. 13Greenwood Genetic Center Greenwood, USA
  14. 14University of Utah, Salt Lake City, USA
  1. Correspondence to:
 Dr M C Speer
 Duke University Medical Center, Box 3445, Durham, NC 27710, USA; marcy{at}chg.duhs.duke.edu

Abstract

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.

  • AD, Alzheimer’s disease
  • GDA, Genetic Data Analysis program
  • HD, Hirschsprung’s disease
  • Hetlod, heterogeneity lod score
  • HWE, Hardy-Weinberg equilibrium
  • Mlod, multipoint lod score
  • NTD, neural tube defect
  • QC, quality control
  • SNP, single nucleotide polymorphism
  • Neural tube defects
  • spina bifida
  • birth defects
  • linkage
  • genome screen

https://doi.org/10.1136/jmg.2005.031658

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    Footnotes

    • Competing interests: none declared

    • Broad phenotype includes all types of NTDs; narrow phenotype is restricted to individuals with lumbosacral myelomeningocele. Chromosomes 7 and 11 have Mlod >2.0.

      The NTD Collaborative Group in the USA includes the following centres: Duke University Medical Center (Durham, NC), Children’s Rehabilitation Service (Birmingham, Alabama), University of Alabama (Birmingham, AL), University of North Carolina (Chapel Hill, NC), Carolinas Medical Center (Charlotte, NC), Northwestern University’s Feinberg School of Medicine, Departments of Pediatrics and Neurology, and Children’s Memorial Hospital (Chicago, IL),Institute of Biosciences and Technology, Texas A&M University System Heath Center (Houston TX, Indiana University School of Medicine (Indianapolis, IN), University of Wisconsin Hospitals (Madison, WI), Virginia Commonwealth University (Richmond, VA), University of Utah (Salt Lake City, UT), and Shriner’s Hospital (Springfield, MA)