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

• 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
• 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

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.

摘要 口面部裂(OFC)是最常见的颅面先天性畸形，可分为两类 大组：上唇裂伴或不伴腭裂(CL/P)和单纯腭裂(CP)。这些出生 缺陷很容易辨认，虽然介入治疗的长期预后良好，但也会受到影响。 个人通常会接受多次手术，可能有牙列异常，反复耳部感染， 言语和听力问题，并且在晚年有较高的发病率和死亡率。尽管分享了一个 腭部缺陷、CP和CL/P在病因上被认为是不同的。很明显，CP和CL/P都是 高度遗传性，虽然已经确定了数十个明确的CL/P遗传风险基因座，但只有几个 CP的基因座已被确定。从历史上看，这些研究是作为一个整体来评估CP病例的，而不是通过 根据受影响的腭部所定义的CP的亚型进行分层。因此，相对缺乏 常见的变异可能是由于表型亚型之间的遗传异质性而稀释了这种能力 以在一起评估时检测相关变量。可替换地和/或同时，CP病因可以是 与其他结构性出生缺陷的关系更密切，如先天性心脏病，通常 由从头突变(DNM)和遗传的大效应大小的罕见变异引起。为了阐明基因 CP的架构在这些可能性的背景下，我将利用来自 由518例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：1)评估CP亚型常见和罕见变异的遗传异质性 利用小鼠胚胎腭部转录数据中的生物学相关基因和2)鉴定 在多基因家庭中罕见变异与疾病分离，随后对分离变异进行调查 在整个队列中。这个队列基于三人组的性质对于发现特别有用，因为它允许共同的 通过传递不平衡检验进行罕见的变异分析，这种检验对种群分层具有很强的稳健性，如 以及高置信度DNM的识别。为了进一步最大化发现能力，这些分析将是 专注于编码符合病原性预测特定标准的变体，以最好地确定潜在的优先顺序 因果变种。在这项研究完成后，我们对慢性支气管炎的遗传风险和每一个 亚型将显著提高。对新风险因素的了解不仅会改善预测， CP的预防和预后，但也阐明了正常和异常的腭部发育的机制。