Integrative Genomic Applications to Understand the Etiology of Unsolved Craniofacial Anomalies
综合基因组应用来了解未解决的颅面异常的病因
基本信息
- 批准号:10390442
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAlgorithmsAreaBinding SitesBiologicalBiologyCRISPR/Cas technologyCartilageCell LineCellsComplexComputer AnalysisCongenital AbnormalityCraniofacial AbnormalitiesDevelopmentDevelopmental BiologyDiagnosisDiseaseEpigenetic ProcessEtiologyExposure toFaceFacultyFoundationsFutureGene Expression ProfilingGenesGeneticGenetic Predisposition to DiseaseGenetic TechniquesGenetic TranscriptionGenetic VariationGenetsGenomeGenomicsGrantHeadHealthcare SystemsInjectionsInstructionLatin AmericanLettersMentorsMessenger RNAMethylationMissense MutationModelingMuscular DystrophiesMutationNosePathogenesisPathogenicityPathway AnalysisPathway interactionsPatientsPatternPeripheralPhasePhenotypePopulationPositioning AttributePublic HealthResearchResourcesSeedsSingle Nucleotide PolymorphismStructureSupervisionTechniquesTechnologyTissuesTrainingUnited StatesVariantWolvesZebrafishcareer developmentcausal variantcohortcongenital anomalycostcraniofacialcraniofacial developmentcraniofacial disorderexomeexperiencefunctional genomicsgene discoverygenetic testinggenome sequencinggenome wide association studygenomic datagenomic variationhands on researchimprovedinsertion/deletion mutationinsightknock-downloss of function mutationmeetingsnew therapeutic targetnovelorofacial cleftpost-doctoral trainingprobandprogramsscreeningskillstraining opportunitytranscriptometranscriptome sequencingwhole genome
项目摘要
Craniofacial abnormalities of the face or head are among the most common birth defects in the United States
and represent a large public health burden. Despite a considerable commitment of resources to research on
the biological etiology underlying a diverse spectrum of craniofacial disorders, the mechanisms leading to
these congenital abnormalities remains largely uncharacterized. Defining the genetic etiology behind these
disorders will not only improve diagnosis and screenings of these disorders, but also improve treatment. In a
recent study, we investigated the genetic etiology behind arhinia, an extremely rare craniofacial malformation
defined by the complete absence of the external nose. Sequencing analysis within this arhinia cohort observed
a significant accumulation of rare heterozygous missense mutations in SMCHD1 in 84% of independent arhinia
cases none of which were present in 60,706 control subjects from the exome aggregation consortium (ExAC).
SMCHD1 is an epigenetic regulator that has been previously been implicated in a digenic form of muscular
dystrophy (FSHD2), but has never been associated with any craniofacial disorders. Aim 1 will explore the
mechanism SMCHD1 causes arhinia and also provide an invaluable training experience in functional genomics
using both epigenetic and transcriptome analyses of patient derived cell lines (Aim 1a) and cartilage tissue
from smchd1 knockdown zebrafish (Aim 1b). Aim 2 will transition into more common craniofacial disorders by
pursuing novel gene discovery in 678 trios with an orofacial cleft (OFC) affected proband that have undergone
whole genome sequencing (WGS). Relying on cutting edge WGS analysis, I will delve into the mutational
spectrum that is cryptic to conventional genetic testing and therefore has never been characterized in an OFC
cohort. Notably, these studies will facilitate a natural transition into the independent R00 phase, which will
bridge the expertise acquired in functional genomics and craniofacial biology during the K99 with my existing
expertise in genome structure to perform the first integrated whole-genome and whole-transcriptome gene
discovery effort in an OFC cohort in Aim 3. This will provide an unprecedented view of both the genome and
transciptome, which will lead to superior gene discovery and mechanistic insight. Overall, this project
represents a unique training opportunity to develop skills in each of my targeted areas of career development
by gaining access and expertise in a diverse set of functional genomics technology and will provide me with
broader exposure to the field of craniofacial genetics. Upon completion of the K99 training proposed in the
grant, I will be well suited for an independent faculty position. Moreover, while the training potential of the
project is high, the studies proposed will have a significant impact on the field of craniofacial genetics and are
ideal to seed future grants as I ultimately develop my own independent research program.
在美国,面部或头部颅面畸形是最常见的出生缺陷之一
项目成果
期刊论文数量(0)
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Harrison Brand其他文献
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{{ truncateString('Harrison Brand', 18)}}的其他基金
Integration of polygenic risk and facial morphometrics to decipher the genetic susceptibility of orofacial clefting
整合多基因风险和面部形态测量来破译口颌裂的遗传易感性
- 批准号:
10342388 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
Integration of polygenic risk and facial morphometrics to decipher the genetic susceptibility of orofacial clefting
整合多基因风险和面部形态测量来破译口颌裂的遗传易感性
- 批准号:
10539314 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
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