Structural Variation analysis of Orofacial Cleft associated genomic regions in African and Asian populations

项目摘要 唇裂是美国第四大最常见的出生缺陷，据了解，每年全球每800名婴儿中就有一人患有唇裂。 儿童优先计划旨在揭示这些疾病的病因并促进数据共享 儿科研究社区。专家驱动的小项目加强加布里埃拉·米勒儿童第一发现 (RFA-RM-22-006)的目的是让专家参与各种活动，以增强 儿童优先计划和/或儿童优先计划生成的儿童癌症和/或结构性出生缺陷基因组数据集 相关的表型数据集和资源“。在这份提案中，我们特别建议深入分析 Kids首次为队列口腔裂收集了精选的数据集：非洲和亚洲血统(253 家庭)目前可通过儿童第一数据门户的CAVATICA框架获得。 目前，对综合征和非综合征OFC的单核苷酸变异(SNV)分析发现 然而，考虑到IRF6、BMP4、MAPK3等基因的功能障碍 变异(SVS)比SNV在人类基因组中占更多的总碱基对变异，我们认为这 主题是这个儿童优先项目中的一个重要组成部分，也是一个缺失的组成部分。探索SVS在社会变革中的作用 OFC表型的表现需要在基因区域之外进行搜索，因为基因间SVS可以 对正常的增强子和转录因子造成损害。我们将探索三种主要的SV类型： 通过寻找不同于Sv的共同和个体SV等位基因来实现缺失、复制和倒置 父母。我们还将研究与OFC相关的基因以及相关的转录因子，Paralog 以及相关的基因间隔区，以充分表征潜在的致病SVS。使用一组预先标识的 包括IRF6在内的39个基因座，我们将密切调查这244个三联体，并使用一个健康的人类队列来筛选 结果(1000个基因组计划第三阶段研究，2504个样本)。该分析将是SNV分析的补充 该数据已经完成，并将为整个基因组提供额外的上下文 风景。我们将向科学界传播我们的工作，并将我们的结果与以前的结果进行比较 拷贝数变化(CNV)文献和共享我们开发的SV三合一工作流，以实现类似的 对加布里埃拉·米勒儿童第一儿科研究计划(儿童优先)的其他数据集进行分析。

Project Summary Cleft lip is the 4th most common birth defect in the U.S. and is known to affect annually one in 800 babies worldwide. The Kids First program aims to uncover the etiology of these diseases and foster data sharing within the pediatric research community. Expert-Driven Small Projects to Strengthen Gabriella Miller Kids First Discovery (RFA-RM-22-006) is intended to “engage experts in a variety of activities that will enhance the utility of childhood cancer and/or structural birth defects genomic datasets generated by the Kids First program and/or associated phenotypic datasets and resources”. In this proposal we specifically propose to analyze in-depth the Kids First curated datasets assembled for the cohort Orofacial Cleft: African and Asian Ancestry (253 Families) currently available through the framework CAVATICA at the Kids First data portal. Currently single nucleotide variation (SNV) analysis in syndromic and non-syndromic OFC has found functional impairments in genes such as IRF6, BMP4, MAPK3, etc. However, considering that Structural Variations (SVs) account for more total base-pair variation in human genomes than SNVs, we argue that this topic is an important and missing component of this Kids First project. Exploring the role of SVs in the manifestation of the OFC phenotype will require a search beyond gene regions, since intergenic SVs can cause impairment to normal enhancers and transcription factors. We will explore three main SV types: deletion, duplication and inversions by looking for common and individual SV alleles that differ from the parents. We will also look at the OFC associated genes along with the related transcription factors, paralogs and associated intergenic regions to fully characterize potentially causative SVs. Using a set of preidentified 39 gene loci including IRF6, we will closely survey the 244 triads and use a healthy human cohort to filter the results (1000 Genome Project Phase 3 study, 2504 samples). This analysis will complement the SNV analysis for this data that has already been completed and will provide additional context for the total genomic landscape. We will disseminate our work to the scientific community and compare our results with previous copy number variation (CNV) literature and share the SV triad workflows we develop to enable a similar analysis on other Gabriella Miller Kids First Pediatric Research Program (Kids First) datasets.