Genetic and Functional Dissection of Congenital Anomalies of the Brain

大脑先天性异常的遗传和功能解剖

基本信息

批准号：
9895872
负责人：
Erica Ellen Davis
金额：
$ 19.82万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895872
关键词：
Ablation Affect Anatomy Anencephaly Animal Model Antisense Oligonucleotides Award Bioinformatics Biological Assay Biological Models Birth Brain CRISPR/Cas technology Candidate Disease Gene Cell physiology Clinical Clinical Research Complement Complex Congenital Abnormality Congenital cerebellar hypoplasia Congenital cerebral hernia Congenital neurologic anomalies Counseling Data Defect Development Diagnosis Diagnostic Dideoxy Chain Termination DNA Sequencing Disease Disease model Dissection Embryo Enrollment Etiology Family Fetus Funding Future Genes Genetic Genetic study Genome Genomics Genotype Healthcare Systems Heterogeneity Holoprosencephaly Human Hybrids Image Investigation Karyotype Knowledge Larva Lead Lesion Light Literature Magnetic Resonance Imaging Messenger RNA Microcephaly Modeling Molecular Molecular Diagnosis Mutate Nervous system structure Neuraxis Neurological observations Newborn Infant Optics Organ Orthologous Gene Parents Pathogenicity Phenotype Physicians Physiological Population Genetics Positioning Attribute Pregnancy Prenatal Diagnosis Preventive Process Proteins Recurrence Resolution Risk Schizencephaly Scientist Signal Pathway Single Nucleotide Polymorphism Structure Syndrome System Technology Testing Therapeutic Translating Translational Research Ultrasonography United States Variant Work Zebrafish base body system brain abnormalities brain malformation causal variant clinical Diagnosis clinical care clinical phenotype exome exome sequencing experience fetal gene discovery genetic analysis genetic disorder diagnosis genetic pedigree genetic variant genome editing genome-wide genomic data human disease human model improved in vivo in vivo Model innovation insertion/deletion mutation knock-down lissencephaly multidisciplinary nervous system development novel outcome forecast perinatal period phenotypic data prenatal prospective rare variant therapeutic target tool zebrafish genome

项目摘要

PROJECT SUMMARY Human brain development remains an incompletely understood process, yet congenital abnormalities of this complex structure affect approximately 3/1,000 pregnancies and more than 2000 newborns annually in the United States, posing a substantial burden on the health care system. Congenital brain abnormalities, hallmarked by vast phenotypic heterogeneity, include but are not limited to holoprosencephaly, schizencephaly, anencephaly, encephalocele, microcephaly, ventriculomegaly, cerebellar hypoplasia, and disorders of cortical development, such as lissencephaly. The paired approach of: (1) prenatal diagnosis using a combination of ultrasound and fetal MRI to characterize aberrant phenotypes; with (2) genetic analysis to determine causal lesions, has greatly improved the ability to accurately counsel families about diagnosis, prognosis, and recurrence risk. More recently, prenatal whole exome sequencing (WES) has been applied in cases of lethal or multiple fetal abnormalities to make a molecular diagnosis that otherwise could not be identified with traditional testing. Pilot data from our group and others using WES show a diagnostic rate of 16- 30% in cases of multiple fetal abnormalities, but only 1-2% in isolated brain abnormalities, indicating a critical need to improve diagnostic capabilities and identify novel genes critical to human brain development. We posit that the overabundance of unresolved fetal cases is in large part due to: (1) a knowledge gap in our understanding of the repertoire of genotypes underlying brain abnormalities with prenatal onset; and (2) limitations of population genetics to establish causality of rare variants in novel candidate genes. Here, two CTSA-funded teams who are at the forefronts of prenatal genetic diagnostics and in vivo zebrafish modeling of human disease, at UNC and Duke, respectively, will team up to overcome the current challenges of diagnosing brain abnormalities with a prenatal onset. We will intersect exome- and genome-wide variation data with experimentally tractable and relevant model systems, zebrafish (Danio rerio). We hypothesize that bioinformatics filters using prenatal WES data will reveal novel candidate genes, which can be applied to a zebrafish model to generate initial discoveries critical to human brain development and translate into improved clinical care. First, we will perform bioinformatic analysis of 10 clinically ascertained fetuses with CNS anomalies and their parents using a tiered filtering strategy; and we will apply this analysis paradigm iteratively to 32 prospectively enrolled fetuses and their families. Second, we will establish relevance of candidate genes to brain development and determine variant pathogenicity using state-of-the-art genome editing and phenotyping tools in zebrafish. Completion of our work will expand our understanding of the molecular processes governing prenatal brain development; establish a clinical-research hybrid platform readily applicable to other anatomical organ defects detectable by fetal imaging; and build a suite of animal models of aberrant CNS development with potential for future use in therapeutic target identification.

项目摘要人脑发育仍然是一个不完全理解的过程，但先天性异常复杂的结构每年在美国，对医疗保健系统造成了重大负担。先天性大脑异常，以广阔的表型异质性为标志，包括但不限于全脑脑，精神分裂，Ancephaly，脑核，小头畸形，心室肿瘤，小脑呼吸症和皮质发育的疾病，例如Lissencephaly。配对方法的：（1）使用产前诊断超声和胎儿MRI的组合以表征异常表型；（2）遗传分析确定因果病变，已大大提高了准确咨询家庭诊断的能力，预后和复发风险。最近，在致命或多个胎儿异常的病例，以做出分子诊断，否则不可能是通过传统测试确定。来自我们小组和其他使用WE的其他人的飞行员数据显示16--的诊断率为16- 在多种胎儿异常的情况下，有30％，但孤立的脑异常中只有1-2％，表明关键需要提高诊断能力并确定对人脑发育至关重要的新基因。我们认为未解决的胎儿病例的过度在很大程度上是由于：（1）我们的知识差距了解产前发作的脑异常基因型的曲目；（2）种群遗传学在新候选基因中建立稀有变异的因果关系的局限性。在这里，两个 CTSA资助的团队处于产前遗传诊断和体内斑马鱼建模的最前沿分别在UNC和Duke的人类疾病将联手克服当前诊断的挑战发作产前的脑异常。我们将与全基因组和全基因组变异数据相交实验可牵引和相关的模型系统，斑马鱼（Danio Rerio）。我们假设这一点使用产前WES数据的生物信息学过滤器将揭示新的候选基因，可以应用于A 斑马鱼模型生成对人脑发育至关重要的初始发现并转化为改进的临床护理。首先，我们将对CNS的10个临床确定的胎儿进行生物信息学分析异常及其父母使用分层的过滤策略；我们将在迭代上应用此分析范式到32名前瞻性招募的胎儿及其家人。其次，我们将建立候选基因的相关性使用最先进的基因组编辑和斑马鱼中的表型工具。完成工作将扩大我们对分子的理解处理产前大脑发育的过程；轻松建立一个临床研究混合动力平台适用于可通过胎儿成像检测到的其他解剖器官缺陷；并建立一套动物模型异常的CNS开发具有未来在治疗靶标识别中使用的潜力。