Genetics of Sagittal Craniosynostosis

矢状位颅缝早闭的遗传学

• 批准号: 9228212
• 负责人: Barbu Razvan Gociman
• 金额: $ 7.56万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-12 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9228212
• 关键词: Address; Affect; Area; Blood; Blood specimen; Cephalic; Clinic; Clinical; Collection; Congenital Disorders; Congenital abnormal Synostosis; Craniosynostosis; DNA Sequence Alteration; Data Analyses; Deformity; Development; Disease; Dizygotic Twins; Embryo; Etiology; Family; Functional disorder; Genes; Genetic; Genetic Counseling; Genetic Models; Genetic Predisposition to Disease; Genetic Variation; Genetic study; Impairment; Incidence; Individual; Inherited; Intracranial Hypertension; Joint structure of suture of skull; Lead; Loss of Heterozygosity; Modality; Modeling; Monozygotic twins; Mosaicism; Mutation; Neurocognitive; Parents; Patients; Pediatric Hospitals; Phenotype; Population Database; Positioning Attribute; Pregnancy; Process; Public Health; Resources; Sampling; Scaphycephaly; Somatic Mutation; Surgical sutures; Syndrome; Testing; Time; Tissue Sample; Tissues; Twin Multiple Birth; Twin Studies; Universities; Utah; Validation; base; bone; clinical practice; cost; craniofacial; design; effective therapy; exome sequencing; genetic pedigree; genome sequencing; high risk; innovation; neoplastic; next generation sequencing; offspring; peripheral blood; premature; success; suture fusion; symptom treatment; tissue mosaicism; whole genome

PROJECT SUMMARY / ABSTRACT Nonsyndromic sagittal craniosynostosis represents the most common cause of cranial vault deformity, with an estimated incidence of 0.4-1/1000. The premature sagittal suture fusion can lead to increased intracranial pressure and impairment in the neurocognitive development. The cost associated with the management of the condition is substantial. Despite an obvious strong genetic base, the etiology of non-syndromic sagittal craniosynostosis remains obscure, therefore only symptomatic treatment modalities currently exist. Recently it has been shown that an important fraction of de-novo mutations presumed to be germline in fact occurred either post-zygotically in the offspring or were inherited as a consequence of low-level mosaicism in one of the parents. We put forth the hypothesis that a loss-of-heterozygosity, two-hit, recessive model is responsible for the development of nonsyndromic sagittal craniosynostosis. One genetic mutation is germline transmitted and the other occurs in somatically, in mosaic fashion, very early in development at the level of the tissues that form the sagittal suture. The first aim of the proposal is design to identify the de-novo mutations in genes regulating bone fusion at the level of the sagittal suture that are responsible for the premature suture closure. Exome sequencing of paired blood and bony tissue from the fused sagittal suture of affected individuals will be done to identify such mutations. Data analysis and directed sequencing of samples from multiple additional individuals for validation of findings will be performed. The second aim will address the genetic germline contribution to the development of sagittal synostosis. Taking advantage by the unique resource represented by the Utah Population Database, multiplex families from our clinical practice that show aggregation of nonsyndromic sagittal synostosis will be expanded. Whole genome sequencing of blood samples and data analysis will be performed in affected and unaffected individuals from these high-risk expanded pedigrees. Success in identification of genetic variation in patients with sagittal synostosis will create the opportunity for understanding the pathophysiology of the disease process. This significance of the study is that understanding the genetic etiology of craniosynostosis will allow personalized genetic counseling and implementation of therapies specific to the mechanism of disease.

项目总结/摘要 非综合征性矢状颅缝早闭是颅穹窿畸形最常见的原因， 估计发病率为0.4-1/1000。过早矢状缝融合可导致颅内 神经认知发育的压力和障碍。与管理有关的费用 条件是实质性的。尽管有明显的强大遗传基础，非综合征性矢状面 颅缝早闭仍然不清楚，因此目前仅存在对症治疗方式。 最近的研究表明，事实上，被认为是生殖系突变的一个重要部分， 发生在合子后的后代，或作为低水平镶嵌的结果遗传， 其中一个家长我们提出了一个假设，即杂合性丢失，两次击中，隐性模型是 导致了非综合征性矢状颅缝早闭症的发生。一种基因突变是生殖细胞 传播和其他发生在体细胞，在马赛克的方式，非常早期的发展水平， 形成矢状缝的组织 该提案的第一个目的是设计鉴定在骨融合中调节基因的从头突变， 矢状缝的水平，负责过早缝合。外显子组测序 将从受影响个体的融合矢状缝中采集血液和骨组织， 突变。对来自多个额外个体的样本进行数据分析和定向测序以进行验证 将进行调查。 第二个目标是解决遗传生殖细胞的矢状骨结合的发展。 利用以犹他州人口数据库为代表的独特资源， 从我们的临床实践，显示聚集性的非综合征性矢状骨缝将扩大。整个 将在受影响和未受影响的患者中进行血液样本的基因组测序和数据分析。 从这些高风险的扩展谱系中分离个体。 在矢状面骨性结合患者中成功鉴定遗传变异将为以下方面创造机会： 了解疾病过程的病理生理学。这项研究的意义在于， 颅缝早闭的遗传病因学将允许个性化的遗传咨询和实施， 针对疾病机制的特定疗法。