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Genomic Risk Variants in Orofacial Clefting: Discovery and Functional Validation

口颌面裂的基因组风险变异：发现和功能验证

基本信息

批准号：
10560719
负责人：
Mary L. Marazita
金额：
$ 75.01万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2022-12-21 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560719
关键词：
Affect Biological Models Biology CRISPR/Cas technology Caring Child Cleft Lip Cleft Palate Code Colon Carcinoma Complex Congenital Abnormality Coupled Craniofacial Abnormalities Data Data Set Developing Countries Development Dideoxy Chain Termination DNA Sequencing Disease Embryo Environmental Exposure Etiology Face Family Gene Expression Genes Genomics Genotype Goals Harvest Heritability Histology Hospitals Human Incidence Individual Infant Mortality Investigation Life Link Malignant neoplasm of brain Medical Mental Health Morbidity - disease rate Morphology Mus Mutation Newborn Infant Nucleotides Operative Surgical Procedures Orthodontic Parents Pathway interactions Phenotype Public Health Publishing Research Resources Risk Signal Transduction Single Nucleotide Polymorphism Speech Therapy Structural Congenital Anomalies Structure System Testing The Jackson Laboratory Translating Treatment Cost Validation Variant X-Ray Computed Tomography causal variant comorbidity cost effective craniofacial de novo mutation digital feeding flexibility follow-up gene discovery genetic architecture genetic variant genome sequencing genome wide association study genome-wide high risk improved innovation insertion/deletion mutation malignant breast neoplasm member microCT mortality mouse model novel novel strategies orofacial cleft rare variant risk prediction risk variant targeted sequencing whole genome

项目摘要

ABSTRACT Orofacial clefts (OFCs, comprising cleft lip-CL, cleft palate-CP, or both-CLP) are the most common craniofacial anomalies in humans, affecting approximately 1 in 700 newborns worldwide, and are thus one of the most common structural birth defects. There are substantial public health impacts of OFCs, due to associated morbidity and mortality. An average child with an OFC initially faces feeding difficulties, undergoes 6 surgeries, spends 30 days in hospital, receives 5 years of orthodontic treatment, and participates in ongoing speech therapy, leading to an estimated total lifetime treatment cost of about $200,000. Further, individuals born with an OFC have an increased incidence of mental health problems, higher mortality rates at all stages of life and higher risk for other disorders (notably including breast, brain, and colon cancers), and higher infant mortality (particularly in developing countries where access to medical care may be limited). OFCs are etiologically complex, resulting from genetic variants, environmental exposures, and their interactions. Genome wide association studies coupled with sequencing results have identified at least 35 genes/regions achieving genome-wide significance from multiple independent studies but these results only account for a fraction of heritability. Rare variant studies are emerging with the availability of whole genome sequencing (WGS) datasets, but functional validation of rare variants is essential to generate the support necessary to link these genes/variants to OFCs, to understand the biology behind OFCs, to translate association signals into accurate risk predictions, and ultimately to develop and/or improve therapies. The overall goal of this new collaborative project is to identify the functional significance of rare risk variants identified in our large resource of OFC families and controls. The proposed aims of this new project will help achieve our overall goal. We will utilize our OFC WGS resources (2,078 OFC case/parent trios) to discover new genomic risk variants with innovative analyses emphasizing single nucleotide variants (SNVs), structural variants (SVs), and indels. For functional validation, this new project will take advantage of the high-efficiency and flexibility of CRISPR/Cas9 technology: research team members at the Jackson Laboratory have developed a novel approach to rapidly validate putative causative variants in the mouse, thus enabling the use of a mammalian system for both variant validation and for more detailed investigation of the resulting cleft phenotypes.

摘要