Complex trait analysis of ventricular septal defects caused by Nkx2-5 mutation

Julia B. Winston, Claire E. Schulkey, Iuan Bor D. Chen, Suk D. Regmi, Maria Efimova, Jonathan M. Erlich, Courtney A. Green, Ashley Aluko, Patrick Y. Jay

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28 Scopus citations


Background- The occurrence of a congenital heart defect has long been thought to have a multifactorial basis, but the evidence is indirect. Complex trait analysis could provide a more nuanced understanding of congenital heart disease. Methods and Results- We assessed the role of genetic and environmental factors on the incidence of ventricular septal defects (VSDs) caused by a heterozygous Nkx2-5 knockout mutation. We phenotyped <3100 hearts from a second-generation intercross of the inbred mouse strains C57BL/6 and FVB/N. Genetic linkage analysis mapped loci with lod scores of 5 to 7 on chromosomes 6, 8, and 10 that influence the susceptibility to membranous VSDs in Nkx2-5 +/- animals. The chromosome 6 locus overlaps one for muscular VSD susceptibility. Multiple logistic regression analysis for environmental variables revealed that maternal age is correlated with the risk of membranous and muscular VSD in Nkx2-5+/- but not wild-type animals. The maternal age effect is unrelated to aneuploidy or a genetic polymorphism in the affected individuals. The risk of a VSD is not only complex but dynamic. Whereas the effect of genetic modifiers on risk remains constant, the effect of maternal aging increases over time. Conclusions- Enumerable factors contribute to the presentation of a congenital heart defect. The factors that modify rather than cause congenital heart disease substantially affect risk in predisposed individuals. Their characterization in a mouse model offers the potential to narrow the search space in human studies and to develop alternative strategies for prevention.

Original languageEnglish
Pages (from-to)293-300
Number of pages8
JournalCirculation: Cardiovascular Genetics
Issue number3
StatePublished - Jun 2012


  • Congenital heart defects
  • Genetic modifier
  • Genetic variation
  • Maternal age
  • Nkx2-5


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