High Throughput Genotyping and DNA Sequencing for Studying the Genetic Contributions to Human Disease: Discovering the genetic basis of cleft palate (Leslie)

腭裂（CP）是一种常见的颅面结构性先天缺陷，由腭裂（分离口腔和鼻腔的结构）不完全闭合引起，导致进食、语言和听力问题。先天性先天性唇腭裂占所有唇腭裂（OFCs）的33%，约占全世界出生婴儿的1 / 1500。虽然CP通常与其他类型的唇腭裂（如唇裂或腭裂）归为一类，但CP在胚胎学和流行病学上是不同的，表明其病因独特。一级亲属中CP复发的风险比人群风险高50倍以上，提示有很强的遗传成分。然而，关于CP的遗传研究一直缺乏。三个全基因组关联研究和荟萃分析只揭示了两个相关位点，这两个位点在任何群体的遗传力中都占不了很大一部分。常见变异相关性的缺乏表明，CP的病因可能与其他先天性异常（如先天性心脏病）相似，后者通常由新生突变、遗传罕见变异和拷贝数变异引起。我们建议通过在表型良好的多种族队列中对病例-亲本三胞胎进行全基因组测序来阐明CP的遗传结构。此外，通过将这些数据与现有的唇腭裂和其他结构性出生缺陷的全基因组测序数据相结合，我们将能够确定与CP相关的共同途径或条件。为了实现这些目标，我们从我们的多学科联盟中收集了世界上最大的CP三胞胎队列，该联盟汇集了OFCs，测序，统计遗传学和风险变异的功能验证方面的专业知识。该项目有望迅速推进我们对CP遗传病因的理解，并将风险转化为家庭风险，并可能改善对CP患者的诊断和治疗。

Cleft palate (CP) is a common craniofacial structural birth defect caused by the incomplete closure of the palate (the structure separating the oral and nasal cavities), resulting in feeding, speech, and hearing problems. CP accounts for 33% of all orofacial clefts (OFCs) or approximately 1 in 1500 babies born worldwide. Although CP is commonly grouped with other types of orofacial clefts (e.g. cleft lip or cleft with cleft palate), CP is embryologically and epidemiologically distinct, suggesting a unique etiology. The risk of CP recurrence in first degree relatives is over 50-fold higher than the population risk, suggesting a strong genetic component. However, there have been a dearth of genetic studies for CP. Three well-powered genome-wide association studies and meta-analysis have revealed only two associated loci, neither of which account for a large portion of the genetic heritability in any population. The lack of common variant associations suggest that the etiology of CP may be similar to other congenital anomalies, such as congenital heart disease, which often result from de novo mutations, inherited rare variants, and copy number variation. We propose to elucidate the genetic architecture of CP by performing whole genome sequencing of case-parent trios in a well-phenotyped, multi-ethnic cohort. Further, by integrating these data with existing whole genome sequencing data for cleft lip and palate and other structural birth defects, we will be able to identify common pathways or conditions associated with CP. To accomplish these goals, we have assembled the largest cohort of CP trios in the world, drawn from the resources of our multidisciplinary consortium that brings together expertise on OFCs, sequencing, statistical genetics, and functional validation of risk variants. This project is poised to rapidly advance our understanding of the genetic etiology of CP and translate risk to families, and may lead to improved diagnosis and treatment for individuals with CP.