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:
- 金额:$ 75.01万
- 依托单位:
- 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:
- 关键词:AffectBiological ModelsBiologyCRISPR/Cas technologyCaringChildCleft LipCleft PalateCodeColon CarcinomaComplexCongenital AbnormalityCoupledCraniofacial AbnormalitiesDataData SetDeveloping CountriesDevelopmentDideoxy Chain Termination DNA SequencingDiseaseEmbryoEnvironmental ExposureEtiologyFaceFamilyGene ExpressionGenesGenomicsGenotypeGoalsHarvestHeritabilityHistologyHospitalsHumanIncidenceIndividualInfant MortalityInvestigationLifeLinkMalignant neoplasm of brainMedicalMental HealthMorbidity - disease rateMorphologyMusMutationNewborn InfantNucleotidesOperative Surgical ProceduresOrthodonticParentsPathway interactionsPhenotypePublic HealthPublishingResearchResourcesRiskSignal TransductionSingle Nucleotide PolymorphismSpeech TherapyStructural Congenital AnomaliesStructureSystemTestingThe Jackson LaboratoryTranslatingTreatment CostValidationVariantX-Ray Computed Tomographycausal variantcomorbiditycost effectivecraniofacialde novo mutationdigitalfeedingflexibilityfollow-upgene discoverygenetic architecturegenetic variantgenome sequencinggenome wide association studygenome-widehigh riskimprovedinnovationinsertion/deletion mutationmalignant breast neoplasmmembermicroCTmortalitymouse modelnovelnovel strategiesorofacial cleftrare variantrisk predictionrisk varianttargeted sequencingwhole 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Mary L. Marazita其他文献
Diagnosing subtle palatal anomalies: Validation of video-analysis and assessment protocol for diagnosing occult submucous cleft palate
- DOI:
10.1016/j.ijporl.2017.06.009 - 发表时间:
2017-09-01 - 期刊:
- 影响因子:
- 作者:
Ryan Rourke;Seth M. Weinberg;Mary L. Marazita;Noel Jabbour - 通讯作者:
Noel Jabbour
Mary L. Marazita的其他文献
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{{ truncateString('Mary L. Marazita', 18)}}的其他基金
Differences between the sexes among genetic variants affecting orofacial cleft birth defect risk
影响口颌裂出生缺陷风险的基因变异的性别差异
- 批准号:
10602447 - 财政年份:2022
- 资助金额:
$ 75.01万 - 项目类别:
Differences between the sexes among genetic variants affecting orofacial cleft birth defect risk
影响口颌裂出生缺陷风险的基因变异的性别差异
- 批准号:
10420286 - 财政年份:2022
- 资助金额:
$ 75.01万 - 项目类别:
Enhanced Data from Orofacial Cleft Trios to Strengthen the Gabriella Miller Kids First (GMKF) Discovery Goals
口面裂三重奏的增强数据可强化 Gabriella Miller Kids First (GMKF) 发现目标
- 批准号:
10599333 - 财政年份:2022
- 资助金额:
$ 75.01万 - 项目类别:
Association Study of Orofacial Cleft Risk Variants across All of Us Cancer Diagnoses
所有癌症诊断中口面裂风险变异的关联研究
- 批准号:
10654330 - 财政年份:2022
- 资助金额:
$ 75.01万 - 项目类别:
Human genomics analysis interface for FaceBase 2
FaceBase 2 的人类基因组学分析接口
- 批准号:
9050666 - 财政年份:2014
- 资助金额:
$ 75.01万 - 项目类别:
Human genomics analysis interface for FaceBase 2
FaceBase 2 的人类基因组学分析接口
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9258429 - 财政年份:2014
- 资助金额:
$ 75.01万 - 项目类别:
Human genomics analysis interface for FaceBase 2
FaceBase 2 的人类基因组学分析接口
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8724830 - 财政年份:2014
- 资助金额:
$ 75.01万 - 项目类别:
Extending the Phenotype of Nonsyndromic Orofacial Clefts
扩展非综合征性口面裂的表型
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7909897 - 财政年份:2009
- 资助金额:
$ 75.01万 - 项目类别:
3D Analysis of Normal Facial Variation: Data Repository and Genetics (Research)
正常面部变异的 3D 分析:数据存储库和遗传学(研究)
- 批准号:
7767242 - 财政年份:2009
- 资助金额:
$ 75.01万 - 项目类别:
3D Analysis of Normal Facial Variation: Data Repository and Genetics (Research)
正常面部变异的 3D 分析:数据存储库和遗传学(研究)
- 批准号:
7933834 - 财政年份:2009
- 资助金额:
$ 75.01万 - 项目类别:
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