Genomics of Cleft Palate

项目概要/摘要 腭裂（CP）是一种常见的颅面结构性出生缺陷， 腭（分隔口腔和鼻腔的结构），导致进食、言语和听觉 问题CP占所有口面裂（OFC）的33%，或约1/1500出生的婴儿 国际吧虽然CP在口语中用于指所有类型的口面裂（例如唇裂或唇裂 腭），CP是胚胎学和流行病学不同的口面裂涉及嘴唇，这表明， 独特的遗传病因一级亲属中CP复发的风险比一级亲属高50倍以上。 人口风险，表明有很强的遗传成分。然而，一直缺乏遗传学研究 对于CP。三项强有力的全基因组关联研究和荟萃分析显示， 相关基因座，这两个都没有占任何群体遗传力的很大一部分。的 缺乏共同的变异关联表明CP的病因可能与其他先天性 异常，如先天性心脏病，这往往是由于从头突变，遗传罕见 变异和结构变异。我们建议阐明CP的遗传结构：（1）分析 全基因组测序中的编码和非编码从头，遗传和结构变异超过550 在一个表型良好的多种族CP队列中的病例-父母三人组;（2）将这些数据与 来自小鼠和人腭的转录组学数据，以鉴定特定CP亚型的潜在途径;以及 (3)确定CP风险变体/基因是否在其他出生缺陷和发育中显示多效性效应 紊乱该项目有望迅速推进我们对CP遗传病因学的理解， 将风险转移到家庭，并可能导致改善CP患者的诊断和治疗。

PROJECT SUMMARY/ABSTRACT 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 colloquially used to refer to all types orofacial clefts (e.g. cleft lip or cleft with cleft palate), CP is embryologically and epidemiologically distinct from orofacial clefts involving the lip, suggesting a unique genetic 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 structural variation. We propose to elucidate the genetic architecture of CP by: (1) analyzing coding and noncoding de novo, inherited, and structural variants in whole genome sequencing of over 550 case-parent trios in a well-phenotyped, multi-ethnic cohort with CP; (2) integrating these data with transcriptomic data from mouse and human palate to identify pathways underlying specific CP subtypes; and (3) determine if CP risk variants/genes show pleiotropic effects in other birth defects and developmental disorders. 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.