Genomics of Cleft Palate

腭裂基因组学

• 批准号: 10624952
• 负责人: ELIZABETH JANE LESLIE
• 金额: $ 71.19万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624952
• 关键词: ATAC-seq; Address; Affect; Benchmarking; Biological; ChIP-seq; Cleft Lip; Cleft Palate; Cleft lip with or without cleft palate; Clinical; Code; Collection; Congenital Abnormality; Data; Data Set; Dental; Development; Developmental Process; Diagnosis; Epidemiology; Etiology; Face; Family; Family Study; Female; Financial Hardship; First Degree Relative; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic study; Genomics; Goals; Hearing; Hearing problem; Heart Abnormalities; Heritability; Heterogeneity; Human; Human Genetics; Individual; Inherited; Knowledge; Lip structure; Mediating; Meta-Analysis; Molecular; Mus; Nasal cavity; Neurodevelopmental Disorder; Nucleotides; Operative Surgical Procedures; Oral cavity; Palate; Parents; Pathway interactions; Phenotype; Population; Population Heterogeneity; Prevention; Prognosis; Recurrence; Research; Resources; Risk; Sampling; Sex Bias; Soft Palate; Speech; Structural Congenital Anomalies; Structure; Syndrome; Techniques; Tissues; Translating; Untranslated RNA; Variant; cohort; comorbidity; congenital anomaly; congenital heart disorder; craniofacial; data integration; de novo mutation; developmental disease; feeding; functional genomics; gene discovery; genetic architecture; genetic predictors; genetic variant; genome sequencing; genome wide association study; genomic data; high risk; high risk population; human RNA sequencing; human data; improved; insight; male; multi-ethnic; novel; orofacial cleft; palate repair; pleiotropism; precision genetics; rare variant; recruit; repaired; risk variant; single cell sequencing; transcriptome; transcriptome sequencing; transcriptomics; whole genome

PROJECT SUMMARY/ABSTRACT Cleft palate (CP) is a common craniofacial structural birth defect caused by the incomplete closure of the palate (the structure separating the oral and nasal cavities), resulting in feeding, speech, and hearing problems. CP accounts for 33% of all orofacial clefts (OFCs) or approximately 1 in 1500 babies born worldwide. Although CP is colloquially used to refer to all types orofacial clefts (e.g. cleft lip or cleft with cleft palate), CP is embryologically and epidemiologically distinct from orofacial clefts involving the lip, suggesting a unique genetic etiology. The risk of CP recurrence in first degree relatives is over 50-fold higher than the population risk, suggesting a strong genetic component. However, there have been a dearth of genetic studies for CP. Three well-powered genome-wide association studies and meta-analysis have revealed only two associated loci, neither of which account for a large portion of the genetic heritability in any population. The lack of common variant associations suggest that the etiology of CP may be similar to other congenital anomalies, such as congenital heart disease, which often result from de novo mutations, inherited rare variants, and structural variation. We propose to elucidate the genetic architecture of CP by: (1) analyzing coding and noncoding de novo, inherited, and structural variants in whole genome sequencing of over 550 case-parent trios in a well-phenotyped, multi-ethnic cohort with CP; (2) integrating these data with transcriptomic data from mouse and human palate to identify pathways underlying specific CP subtypes; and (3) determine if CP risk variants/genes show pleiotropic effects in other birth defects and developmental disorders. This project is poised to rapidly advance our understanding of the genetic etiology of CP and translate risk to families, and may lead to improved diagnosis and treatment for individuals with CP.

项目摘要/摘要 left裂（CP）是一种常见的颅面结构出生缺陷 口感（将口腔和鼻腔分开的结构）导致喂食，语音和听力 问题。 CP占所有口腔裂口（OFC）的33％，约1500名婴儿出生 全世界。尽管CP被通用用于参考所有类型的口面裂口（例如，唇裂或left裂 口感），CP在胚胎学和流行病学上与涉及嘴唇的口面裂缝不同，这表明 独特的遗传病因。一级亲戚在一级亲戚中复发的风险比 人口风险，表明有强大的遗传成分。但是，遗传研究已经缺乏 对于CP。三项全基因组的关联研究和荟萃分析仅显示了两个 相关的基因座，在任何人群中，哪一个都不是遗传遗传力的很大一部分。这 缺乏共同的变体关联表明，CP的病因可能与其他先天性相似 异常（例如先天性心脏病）通常是由从头突变引起的，遗传了罕见 变体和结构变化。我们建议阐明CP的遗传结构：（1）分析 整个基因组测序中的编码和非编码从头开始，遗传和结构变体超过550 在具有CP的良好，多种族的队列中，案例父母三重奏； （2）将这些数据与 来自小鼠和人pa的转录组数据以识别特定CP亚型的途径；和 （3）确定CP风险变异/基因是否在其他出生缺陷和发育中显示出多效性 疾病。该项目有望快速促进我们对CP遗传学学的理解和 将风险转化为家庭，并可能会改善CP患者的诊断和治疗。