Genomics of Cleft Palate

腭裂基因组学

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要腭裂（CP）是一种常见的颅面部结构性出生缺陷，是由于腭裂闭合不完全引起的。腭（分隔口腔和鼻腔的结构），负责进食、言语和听力问题。 CP 占所有口面部裂 (OFC) 的 33%，即大约每 1500 个出生婴儿中就有 1 个患有 CP 全世界。尽管 CP 通俗地用于指所有类型的口面部裂（例如唇裂或裂口）腭），CP 在胚胎学和流行病学上与涉及嘴唇的口面裂不同，这表明独特的遗传病因学。一级亲属发生 CP 复发的风险比亲属高 50 倍以上人群风险，表明有很强的遗传因素。然而，遗传研究却十分匮乏。为了CP。三项强有力的全基因组关联研究和荟萃分析仅揭示了两种相关基因座，这两个基因座都不占任何人群遗传力的很大一部分。这缺乏常见的变异关联表明 CP 的病因可能与其他先天性遗传病相似异常，例如先天性心脏病，通常是由新突变引起的，遗传性罕见变异和结构变异。我们建议通过以下方式阐明 CP 的遗传结构：（1）分析超过 550 个全基因组测序中的编码和非编码从头变异、遗传变异和结构变异表型良好的多种族 CP 队列中的病例父母三人组； (2) 将这些数据与来自小鼠和人类上颚的转录组数据，用于识别特定 CP 亚型的潜在途径；和 (3) 确定 CP 风险变异/基因是否在其他出生缺陷和发育中表现出多效性失调。该项目有望迅速增进我们对 CP 遗传病因学的理解，将风险转嫁给家庭，并可能改善脑瘫患者的诊断和治疗。