出生缺陷是相对普遍的先天性结果，对受影响个体、家庭和社区都有重大影响。对这些疾病采取有效的预防和治疗策略需要充分了解其病因，包括基因和环境因素。在家族性和综合症形式的出生缺陷的基因定位方面已经取得了巨大进展。然而，大多数的出生缺陷案例被认为是非综合症的，并被认为是由多因素的基因环境相互作用所致。虽然在阐明这些病因复杂的疾病的基因景观方面取得了重大进展，但重大的生物学和技术限制阻碍了对环境风险因素的精细了解。在出生缺陷病因中定义具体的基因环境相互作用更加具有挑战性。然而，已经取得了进展，包括关键概念的证明和解决复杂的基因环境相互作用的新的概念和技术方法的开发。在本文中，我们讨论了多因素性出生缺陷病因的当前观点，并将其与其他涉及基因环境相互作用的疾病进行比较，包括原发性免疫缺陷和癌症。我们描述了各种模型系统如何阐明多因素病因的机制以及这些模型的各自优点和缺点。最后，提出了未来重点研究领域的建议。版权所有 ©2023 Elsevier Inc。保留所有权利。

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.Copyright © 2023 Elsevier Inc. All rights reserved.