Sequence-based discovery of risk and modifier variants for orofacial clefts

项目总结 口面部裂(OFC)是人类最常见的头面部出生缺陷，由多种原因引起 遗传和环境风险因素。阐明OFCS的病因学不仅对我们了解 发育生物学和裂隙是如何产生的，但最终是为了改进预防、治疗和 受离岸金融中心影响的个人的预后。外显子组或基因组测序的临床应用正在增长， 但由于缺少可遗传风险的部分，以及对 遗传因子的表型异质性和可变表达。当前提案的目标是 确定对OFCs遗传结构及其实质性表型的罕见变异贡献 异质性。数据来自加布里埃拉·米勒儿童第一儿科研究计划，该计划提供了 对979例OFC三联体进行全基因组测序。我们将对德意志银行进行全面分析 Novo和Rare遗传编码变异，并评估罕见变异作为OFC严重程度的修饰性指标。最后，我们 将WGS数据与IRF6基因座的靶向序列数据相结合，其中包含多个独立的 信号和表型修饰物，以执行基于表型的详细精细图谱分析。这些 分析将进一步深入了解离岸金融中心的遗传结构，并揭示 离岸金融中心的WGS数据。

PROJECT SUMMARY Orofacial clefts (OFCs) are the most common craniofacial birth defect in humans and are caused by multiple genetic and environmental risk factors. Elucidating the etiology of OFCs is critical not only for our knowledge of developmental biology and for how clefts arise, but ultimately for improved prevention, treatment, and prognosis for individuals affected by OFCs. Clinical applications of exome or genome sequencing are growing, but the usability for OFCs is hindered by the missing fraction of heritable risk and a poor understanding of phenotypic heterogeneity and variable expression of genetic factors. The goal of the current proposal is to determine the rare variant contribution to the genetic architecture of OFCs and its substantial phenotypic heterogeneity. The data come from the Gabriella Miller Kids First Pediatric Research Program, which provided whole genome sequencing (WGS) of 979 trios with OFCs. We will perform a comprehensive analysis of de novo and rare inherited coding variation and evaluate rare variants as modifiers of OFC severity. Finally, we will combine WGS data with targeted sequence data for the IRF6 locus, which contains multiple independent signals and phenotypic modifiers, to perform a detailed phenotype-based fine mapping analysis. These analyses will provide further insight into the genetic architecture of OFCs and will reveal the full potential of WGS data for OFCs.