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

Kristen L. Deak, Deborah G. Siegel, Timothy M. George, Simon Gregory, Allison Ashley-Koch*, Marcy C. Speer, Joanna Aben, Arthur Aylsworth, Cynthia Powell, Joanne Mackey, Gordon Worley, Timothy Brei, Connie Buran, Joann Bodurtha, Kathleen Sawin, Mark S. Dias, Philip Mack, Elli Meeropol, Nicole Lasarsky, David McLoneJoy Ito, W. Jerry Oakes, Marion Walker, Paula Peterson, Bermans Iskandar

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)662-669
Number of pages8
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Issue number10
StatePublished - Oct 2008


  • Anencephaly
  • Maternal effect
  • Neural tube defects
  • Recurrence risk
  • Spina bifida

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Embryology
  • Developmental Biology


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