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

项目摘要 口面裂（OFC）是人类最常见的颅面出生缺陷， 遗传和环境风险因素。阐明OFC的病因不仅对我们了解OFC的发病机制至关重要， 发育生物学和裂缝是如何产生的，但最终是为了改善预防，治疗， OFC患者的预后。外显子组或基因组测序的临床应用正在增长， 但是OFC的可用性受到遗传风险缺失部分和对OFC缺乏了解的阻碍。 表型异质性和遗传因子的可变表达。目前提案的目标是 确定罕见变异对OFCs遗传结构的贡献及其实质性表型 异质性这些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 全基因组测序（WGS）的979三与OFC。我们将全面分析 新发和罕见遗传性编码变异，并评估罕见变异作为OFC严重程度的修饰因子。最后我们 将联合收割机WGS数据与IRF6基因座的靶向序列数据相结合， 信号和表型修饰因子，以进行详细的基于表型的精细作图分析。这些 分析将提供对OFCs遗传结构的进一步了解，并将揭示OFCs的全部潜力。 OFC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.