Department of Pediatrics, University of Arkansas for Medical Sciences, College of Medicine, Little Rock.
Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
JAMA Pediatr. 2014 Apr;168(4):371-7. doi: 10.1001/jamapediatrics.2013.4858.
Birth defects are a leading cause of infant morbidity and mortality worldwide. The vast majority of birth defects are nonsyndromic, and although their etiologies remain mostly unknown, evidence supports the hypothesis that they result from the complex interaction of genetic, epigenetic, environmental, and lifestyle factors. Since our last review published in 2002 describing the basic tools of genetic epidemiology used to study nonsyndromic structural birth defects, many new approaches have become available and have been used with varying success. Through rapid advances in genomic technologies, investigators are now able to investigate large portions of the genome at a fraction of previous costs. With next-generation sequencing, research has progressed from assessing a small percentage of single-nucleotide polymorphisms to assessing the entire human protein-coding repertoire (exome)-an approach that is starting to uncover rare but informative mutations associated with nonsyndromic birth defects. Herein, we report on the current state of the genetic epidemiology of birth defects and comment on future challenges and opportunities. We consider issues of study design, and we discuss common variant approaches, including candidate gene studies and genome-wide association studies. We also discuss the complexities embedded in exploring interactions between genes and the environment. We complete our review by describing new and promising next-generation sequencing technologies and examining how the study of epigenetic mechanisms could become the key to unraveling the complex etiologies of nonsyndromic structural birth defects.
出生缺陷是全球导致婴儿发病率和死亡率的主要原因。绝大多数出生缺陷是非综合征性的，尽管其病因大多仍不清楚，但有证据支持这样一种假说，即它们是由遗传、表观遗传、环境和生活方式因素的复杂相互作用引起的。自我们 2002 年发表的上一次综述描述了用于研究非综合征性结构出生缺陷的遗传流行病学基本工具以来，许多新的方法已经出现，并取得了不同程度的成功。通过基因组学技术的快速进步，研究人员现在能够以以前成本的一小部分来研究基因组的大部分。通过下一代测序，研究已经从评估一小部分单核苷酸多态性进展到评估整个人类蛋白质编码组（外显子组）——这种方法开始揭示与非综合征性出生缺陷相关的罕见但有信息的突变。在此，我们报告了出生缺陷遗传流行病学的现状，并评论了未来的挑战和机遇。我们考虑了研究设计的问题，并讨论了常见的变异方法，包括候选基因研究和全基因组关联研究。我们还讨论了探索基因与环境之间相互作用所涉及的复杂性。我们通过描述新的和有前途的下一代测序技术，并研究表观遗传机制的研究如何成为揭示非综合征性结构出生缺陷复杂病因的关键，完成了我们的综述。
