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

项目摘要 唇裂是美国第四大常见的出生缺陷，每年全球每800个婴儿中就有一个受到影响。 儿童第一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，以加强加布里埃拉米勒孩子的第一次发现 （RFA-RM-22-006）旨在“让专家参与各种活动， 由Kids First计划生成的儿童癌症和/或结构性出生缺陷基因组数据集，和/或 相关的表型数据集和资源”。在这份提案中，我们特别提出要深入分析 儿童第一策展的数据集为队列口面裂：非洲和亚洲的唇腭裂（253 家庭），目前可通过框架CAVATICA在儿童第一数据门户网站。 目前，综合征型和非综合征型OFC的单核苷酸变异（SNV）分析发现， 基因如IRF 6、BMP 4、MAPK 3等的功能损伤。然而，考虑到结构 变异（SV）比SNV在人类基因组中占更多的总碱基对变异，我们认为， 主题是这个儿童优先项目的一个重要和缺失的组成部分。探索SV在 OFC表型的表现将需要在基因区域之外进行搜索，因为基因间SV可以 导致正常增强子和转录因子受损。我们将探讨三种主要的SV类型： 缺失、重复和倒位，通过寻找与 父母我们还将研究OFC相关基因沿着相关转录因子、旁系同源物 和相关的基因间区域，以充分表征潜在的致病SV。使用一组预先确定的 包括IRF 6在内的39个基因位点，我们将密切调查244个三联体，并使用健康人群来筛选 结果（1000个基因组计划3期研究，2504个样本）。该分析将补充SNV分析 这些数据已经完成，并将为整个基因组提供额外的背景， 景观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。 拷贝数变异（CNV）文献，并分享我们开发的SV三联体工作流程，以实现类似的 其他Gabriella米勒儿童第一儿科研究计划（儿童第一）数据集的分析。

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.