Research Article

Refinement of 2q and 7p loci in a large multiplex NTD family†

  1. Demetra S. Stamm1,2,
  2. Deborah G. Siegel1,
  3. Lorraine Mehltretter1,
  4. Jessica J. Connelly1,
  5. Alison Trott1,
  6. Nathen Ellis1,
  7. Victoria Zismann3,
  8. Dietrich A. Stephan3,
  9. Timothy M. George4,
  10. Michel Vekemans5,
  11. Allison Ashley-Koch1,
  12. John R. Gilbert6,
  13. Simon G. Gregory1,*,
  14. Marcy C. Speer1,‡

Article first published online: 1 MAY 2008

DOI: 10.1002/bdra.20462

Issue

Birth Defects Research Part A: Clinical and Molecular Teratology

Birth Defects Research Part A: Clinical and Molecular Teratology

Volume 82, Issue 6, pages 441–452, June 2008

Additional Information

How to Cite

Stamm, D. S., Siegel, D. G., Mehltretter, L., Connelly, J. J., Trott, A., Ellis, N., Zismann, V., Stephan, D. A., George, T. M., Vekemans, M., Ashley-Koch, A., Gilbert, J. R., Gregory, S. G. and Speer, M. C. (2008), Refinement of 2q and 7p loci in a large multiplex NTD family. Birth Defects Research Part A: Clinical and Molecular Teratology, 82: 441–452. doi: 10.1002/bdra.20462

Author Information

  1. 1

    Center for Human Genetics, Duke University Medical Center, Durham, North Carolina

  2. 2

    Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina

  3. 3

    Translational Genomics Research Institute, Phoenix, Arizona

  4. 4

    Dell Children's Medical Center, Austin, Texas

  5. 5

    Departement de Genetique Medicale and INSERM U393, Hospital Necker-Enfants Malades, Paris, France

  6. 6

    The Institute for Human Genomics, University of Miami, Miami, Florida

  1. ‡

    Marcy C. Speer died August 4, 2007 after a 2 year battle with breast cancer.

*Center for Human Genetics, Duke University Medical Center, DUMC Box 3445, 595 LaSalle St., Durham, NC 27710

  1. †

    Presented at the 56th annual meeting of the American Society of Human Genetics, October 9–13, 2006, New Orleans, LA.

  2. ‡

    Marcy C. Speer died August 4, 2007 after a 2 year battle with breast cancer.

  3. The NTD Collaborative Group is made up of: Joanna Aben, Children's Rehabilitation Service, Birmingham, AL; Arthur Aylsworth, Cynthia Powell, University of North Carolina, Chapel Hill, NC; Joanne Mackey, Gordon Worley, Duke University Medical Center; Timothy Brei, Connie Buran, Indiana University School of Medicine, Indianapolis, IN; Joann Bodurtha, Kathleen Sawin, Virginia Commonwealth University, Richmond, VA; Philip Mack, Elli Meeropol, Shriner's Hospital, Springfield, MA; Nicole Lasarsky, Carolinas Medical Center, Charlotte, NC; David McLone, Joy Ito, Children's Memorial Hospital, Chicago, IL; W. Jerry Oakes, University of Alabama, Birmingham, AL; Marion Walker, University of Utah, Salt Lake City, UT; Bermans Iskandar, University of Wisconsin Hospitals, Madison, WI.

Publication History

  1. Issue published online: 2 JUN 2008
  2. Article first published online: 1 MAY 2008
  3. Manuscript Accepted: 22 FEB 2008
  4. Manuscript Revised: 17 FEB 2008
  5. Manuscript Received: 22 OCT 2007

Funded by

  • National Institutes of Health. Grant Numbers: HD39948, HD33400, NS39818, ES11375, ES011961, 1F30NS054362

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Keywords:

  • neural tube defects (NTDs);
  • spina bifida;
  • gene mapping;
  • candidate genes;
  • array-CGH

Abstract

BACKGROUND: NTDs are considered complex disorders that arise from an interaction between genetic and environmental factors. NTD family 8776 is a large multigenerational Caucasian family that provides a unique resource for the genetic analysis of NTDs. Previous linkage analysis using a genome-wide SNP screen in family 8776 with multipoint nonparametric mapping methods identified maximum LOD* scores of ∼3.0 mapping to 2q33.1–q35 and 7p21.1–pter. METHODS: We ascertained an additional nuclear branch of 8776 and conducted additional linkage analysis, fine mapping, and haplotyping. Expression data from lymphoblast cell lines were used to prioritize candidate genes within the minimum candidate intervals. Genomic copy number changes were evaluated using BAC tiling arrays and subtelomeric fluorescent in situ hybridization probes. RESULTS: Increased evidence for linkage was observed with LOD* scores of ∼3.3 for both regions. Haplotype analyses narrowed the minimum candidate intervals to a 20.3 Mb region in 2q33.1–q35 between markers rs1050347 and D2S434, and an 8.3 Mb region in 7p21.1–21.3 between a novel marker 7M0547 and rs28177. Within these candidate regions, 16 genes were screened for mutations; however, no obvious causative NTD mutation was identified. Evaluation of chromosomal aberrations using comparative genomic hybridization arrays, subtelomeric fluorescent in situ hybridization, and copy number variant detection techniques within the 2q and 7p regions did not detect any chromosomal abnormalities. CONCLUSIONS: This large NTD family has identified two genomic regions that may harbor NTD susceptibility genes. Ascertainment of another branch of family 8776 and additional fine mapping permitted a 9.1 Mb reduction of the NTD candidate interval on chromosome 7 and 37.3 Mb on chromosome 2 from previously published data. Identification of one or more NTD susceptibility genes in this family could provide insight into genes that may affect other NTD families. Birth Defects Research (Part A), 2008. © 2008 Wiley-Liss, Inc.

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