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

项目概要 口面裂（OFC）是人类最常见的颅面出生缺陷，由多种原因引起 遗传和环境风险因素。阐明 OFC 的病因不仅对于我们了解以下疾病至关重要 发育生物学以及唇裂如何产生，但最终是为了改善预防、治疗和 受 OFC 影响的个体的预后。外显子组或基因组测序的临床应用正在增长， 但 OFC 的可用性受到遗传风险缺失部分和对遗传风险理解不足的阻碍。 表型异质性和遗传因素的可变表达。当前提案的目标是 确定罕见变异对 OFC 遗传结构及其实质性表型的贡献 异质性。数据来自 Gabriella Miller Kids First 儿科研究计划，该计划提供 对 979 个具有 OFC 的三人组进行全基因组测序 (WGS)。我们将对德进行全面分析 新的和罕见的遗传编码变异，并评估罕见变异作为 OFC 严重程度的修饰符。最后，我们 将 WGS 数据与 IRF6 基因座的目标序列数据结合起来，其中包含多个独立的 信号和表型修饰符，以执行详细的基于表型的精细作图分析。这些 分析将进一步深入了解 OFC 的遗传结构，并揭示其全部潜力 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.