Birth defects are relatively common congenital outcomes that significantly impact affected individuals, their families, and communities. Effective development and deployment of prevention and therapeutic strategies for these conditions requires sufficient understanding of etiology, including underlying genetic and environmental causes. Tremendous progress has been made in defining the genetic basis of familial and syndromic forms of birth defects. However, the majority of birth defect cases are considered nonsyndromic and thought to result from multifactorial gene-environment interactions. While substantial advances have been made in elucidating the genetic landscape of these etiologically complex conditions, significant biological and technical constraints have stymied progress toward a refined knowledge of environmental risk factors. Defining specific gene-environment interactions in birth defect etiology is even more challenging. However, progress has been made, including demonstration of critical proofs of concept and development of new conceptual and technical approaches for resolving complex gene-environment interactions. In this review, we discuss current views of multifactorial birth defect etiology, comparing them with other diseases that also involve gene-environment interactions, including primary immunodeficiency and cancer. We describe how various model systems have illuminated mechanisms of multifactorial etiology and these models’ individual strengths and weaknesses. Finally, suggestions for areas of future emphasis are proposed.

Original languageEnglish
Title of host publicationGene-Environment Interactions in Birth Defects and Developmental Disorders
EditorsRobert J. Lipinski, Robert S. Krauss
PublisherAcademic Press Inc.
Number of pages30
ISBN (Print)9780128201572
StatePublished - Jan 2023

Publication series

NameCurrent Topics in Developmental Biology
ISSN (Print)0070-2153


  • Birth defects
  • Environmental risk factors
  • Gene-environment
  • Genetics
  • Nonsyndromic
  • Syndromic
  • Teratogens


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