权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
Harrison Brand
金额：
$ 24.9万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
https://reporter.nih.gov/project-details/10390442
关键词：
Affect Algorithms Area Binding Sites Biological Biology CRISPR/Cas technology Cartilage Cell Line Cells Complex Computer Analysis Congenital Abnormality Craniofacial Abnormalities Development Developmental Biology Diagnosis Disease Epigenetic Process Etiology Exposure to Face Faculty Foundations Future Gene Expression Profiling Genes Genetic Genetic Predisposition to Disease Genetic Techniques Genetic Transcription Genetic Variation Genets Genome Genomics Grant Head Healthcare Systems Injections Instruction Latin American Letters Mentors Messenger RNA Methylation Missense Mutation Modeling Muscular Dystrophies Mutation Nose Pathogenesis Pathogenicity Pathway Analysis Pathway interactions Patients Pattern Peripheral Phase Phenotype Population Positioning Attribute Public Health Research Resources Seeds Single Nucleotide Polymorphism Structure Supervision Techniques Technology Tissues Training United States Variant Wolves Zebrafish career development causal variant cohort congenital anomaly cost craniofacial craniofacial development craniofacial disorder exome experience functional genomics gene discovery genetic testing genome sequencing genome wide association study genomic data genomic variation hands on research improved insertion/deletion mutation insight knock-down loss of function mutation meetings new therapeutic target novel orofacial cleft post-doctoral training proband programs screening skills training opportunity transcriptome transcriptome sequencing whole 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