Original Article

Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects†

  1. Kristen L. Deak1,
  2. Deborah G. Siegel1,
  3. Timothy M. George2,
  4. Simon Gregory1,
  5. Allison Ashley-Koch1,*,
  6. Marcy C. Speer1,‡

Article first published online: 20 OCT 2008

DOI: 10.1002/bdra.20511

Issue

Birth Defects Research Part A: Clinical and Molecular Teratology

Birth Defects Research Part A: Clinical and Molecular Teratology

Special Issue: Remembering Marcy Speer

Volume 82, Issue 10, pages 662–669, October 2008

Additional Information

How to Cite

Deak, K. L., Siegel, D. G., George, T. M., Gregory, S., Ashley-Koch, A. and Speer, M. C. (2008), Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects. Birth Defects Research Part A: Clinical and Molecular Teratology, 82: 662–669. doi: 10.1002/bdra.20511

Author Information

  1. 1

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

  2. 2

    Dell Children's Medical Center of Central Texas, Austin, Texas

  1. ‡

    Marcy C. Speer is deceased.

*Duke University Medical Center, Box 3445, Durham, NC 27710

  1. †

    Presented at the 57th annual meeting of the American Society of Human Genetics, October 23–27, 2007, San Diego, CA.

  2. ‡

    Marcy C. Speer is deceased.

  3. NTD Collaborative Group: 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, Durham, NC); Timothy Brei, Connie Buran (Indiana University School of Medicine, Indianapolis, IN); Joann Bodurtha, Kathleen Sawin (Medical College of Virginia, Richmond, VA); Mark S. Dias (Children's Hospital of Buffalo, Buffalo, NY); 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, Paula Peterson (University of Utah, Salt Lake City, UT); Bermans Iskandar (University of Wisconsin Hospitals, Madison, WI).

Publication History

  1. Issue published online: 20 OCT 2008
  2. Article first published online: 20 OCT 2008
  3. Manuscript Accepted: 30 JUL 2008
  4. Manuscript Revised: 23 JUL 2008
  5. Manuscript Received: 18 APR 2008

Funded by

  • National Institutes of Health. Grant Numbers: NS26630, ES11375

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Keywords:

  • neural tube defects;
  • spina bifida;
  • anencephaly;
  • maternal effect;
  • recurrence risk

Abstract

BACKGROUND:

Neural tube defects (NTDs), including spina bifida and anencephaly, are the second most common birth defect with an incidence of 1/1000. Genetic factors are believed to contribute to NTD risk and family-based studies can be useful for identifying such risk factors.

METHODS:

We ascertained 1066 NTD families (1467 affected patients), including 307 multiplex NTD families. We performed pedigree analysis to describe the inheritance patterns, pregnancy outcomes, and recurrence risks to relatives of various types.

RESULTS:

Myelomeningocele or spina bifida (66.9%) and cranial defects (17.7%) were the most common NTD subtypes observed. The overall male:female ratio for affected individuals was 0.82, and there were even fewer males among individuals with an upper level NTD (0.62). Among twins, 2 of the 5 monozygotic twins and only 3 of 35 dizygotic twins were concordant, while 27% of the same sex twins were concordant, but none of the different sex twins. The estimated 6.3% recurrence risk to siblings (CI 0.04–0.08) is consistent with previous reports. Families with two or more affected individuals show a higher proportion of female transmitters (p = 0.0002). Additionally, the number of affected relatives in maternal compared to paternal lineages was more than double (p = 0.006). There were significantly more miscarriages, infant deaths, and stillborn pregnancies of the maternal aunts and uncles (p < 0.0001) and of first cousins (p = 0.04).

CONCLUSIONS:

Our data provide several lines of evidence consistent with a maternal effect, as well as a sex-influenced effect, in the etiology of NTDs. Birth Defects Research (Part A) 82:662–669, 2008. © 2008 Wiley-Liss, Inc.

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