Identifying novel genetic risks for cleft palate using whole genome sequencing

使用全基因组测序识别腭裂的新遗传风险

基本信息

批准号：
10604812
负责人：
Kelsey Rebecca Robinson Wallace
金额：
$ 4.76万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604812
关键词：
Affect Cleft Palate Cleft lip with or without cleft palate Code Congenital Abnormality Data Data Set Defect Dentition Detection Development Disease Embryo Etiology Evaluation Face Family Family history of Family member First Degree Relative Future Genes Genetic Genetic Heterogeneity Genetic Risk Genotype Goals Hard Palate Hearing Hearing problem Heritability Heterogeneity Individual Inherited Intervention Investigation Knowledge Life Lip structure Live Birth Masks Medical Meta-Analysis Modeling Morbidity - disease rate Mus Nature Nuclear Family Operative Surgical Procedures Palate Parents Pathogenicity Phenotype Population Heterogeneity Prevention Prognosis Recurrence Research Risk Risk Factors Soft Palate Speech Structural Congenital Anomalies Suggestion Testing Time Tissues Variant Wild Type Mouse base causal variant cell type cohort congenital anomaly congenital heart disorder craniofacial de novo mutation ear infection feeding genetic architecture genetic association genetic risk factor genetic variant genome sequencing genome wide association study genome-wide improved insight mortality multiple datasets novel orofacial cleft population stratification power analysis psychosocial rare variant recruit risk variant single-cell RNA sequencing transcriptomics transmission process whole genome

项目摘要

SUMMARY Orofacial clefts (OFCs) are the most common craniofacial congenital anomalies and can be categorized into two large groups: cleft of the upper lip with or without a cleft palate (CL/P) and cleft palate only (CP). These birth defects are easily recognizable, and although the long-term prognosis is favorable with intervention, affected individuals typically undergo multiple surgical procedures, may have abnormal dentition, recurrent ear infections, speech and hearing problems, and have higher rates of morbidity and mortality later in life. Despite sharing a defect of the palate, CP and CL/P are considered etiologically distinct. It is evident that both CP and CL/P are highly heritable, and while dozens of well-established genetic risk loci have been identified for CL/P, only a few loci have been identified for CP. Historically, these studies have evaluated CP cases as a whole, rather than by stratifying by the subtypes of CP that are defined by the part of the palate that is affected. Thus, the relative lack of common variants may be due to genetic heterogeneity among phenotypic subtypes which dilutes the ability to detect associated variants when evaluated together. Alternatively, and/or concurrently, CP etiology may be more closely aligned with that of other structural birth defects, such as congenital heart disease, which often result from de novo mutations (DNMs) and inherited rare variants of large effect sizes. To elucidate the genetic architecture of CP in the context of these possibilities, I will utilize whole genome sequencing (WGS) data from a cohort of 518 CP cases consisting primarily of case-parent trios, and encompassing diverse populations and all subtypes of CP by 1) evaluation of the genetic heterogeneity of CP subtypes for common and rare variants utilizing biologically relevant genes from transcriptomic data of the embryonic mouse palate and 2) identification of rare variants segregating with disease in multiplex families, followed by investigation of segregating variants in the full cohort. The trio-based nature of this cohort is particularly useful for discovery as it allows for common and rare variant analysis by transmission disequilibrium tests, which are robust to population stratification, as well as identification of high confidence DNMs. To further maximize discovery power, these analyses will be focused on coding variants that meet specific criteria for pathogenicity prediction to best prioritize potentially causal variants. Upon completion of this research, our understanding of the genetic risks for CP and each of the subtypes will be significantly advanced. Knowledge of novel risk factors will not only improve prediction, prevention, and prognosis of CP, but also elucidate mechanisms of normal and abnormal palatal development.

概括口面部裂隙（OFC）是最常见的颅面部先天性异常，可分为两类大组：上唇裂伴或不伴腭裂（CL/P）和仅腭裂（CP）。这些诞生缺陷很容易识别，尽管干预的长期预后良好，但受影响的个体通常要接受多次外科手术，可能有牙列异常、反复耳部感染、言语和听力问题，并且在以后的生活中发病率和死亡率更高。尽管共享一个上颚缺陷、CP 和 CL/P 被认为在病因上是不同的。显然 CP 和 CL/P 都是高度遗传，虽然已鉴定出数十个已确定的 CL/P 遗传风险位点，但只有少数 CP 的位点已被确定。从历史上看，这些研究对 CP 病例进行了整体评估，而不是按根据 CP 亚型进行分层，这些亚型由受影响的上颚部分定义。因此，相对缺乏常见变异的出现可能是由于表型亚型之间的遗传异质性，从而削弱了能力一起评估时检测相关变体。或者，和/或同时，CP 病因可能是与其他结构性出生缺陷更密切相关，例如先天性心脏病，通常由从头突变 (DNM) 和遗传性大效应量的罕见变异引起。为了阐明遗传在这些可能性的背景下，我将利用来自 CP 架构的全基因组测序 (WGS) 数据一个由 518 名 CP 病例组成的队列，主要由病例父母三人组组成，涵盖不同的人群和 CP 的所有亚型，通过 1) 评估 CP 亚型常见和罕见变异的遗传异质性利用来自胚胎小鼠上颚转录组数据的生物学相关基因和 2) 鉴定多重家族中与疾病分离的罕见变异，然后对分离变异进行研究在整个队列中。该队列的三重奏性质对于发现特别有用，因为它允许常见的以及通过传递不平衡测试进行的罕见变异分析，这对于群体分层来说是稳健的，例如以及高置信度 DNM 的识别。为了进一步最大化发现能力，这些分析将专注于满足致病性预测特定标准的编码变体，以最好地确定潜在的优先顺序因果变异。完成这项研究后，我们对 CP 的遗传风险和每种疾病的了解亚型将显着进步。了解新的风险因素不仅可以改善预测， CP 的预防和预后，还阐明正常和异常腭发育的机制。