Genomics and functional dissection of fetal brain abnormalities using a prenatal cohort

使用产前队列对胎儿大脑异常进行基因组学和功能解剖

• 批准号: 10277107
• 负责人: Neeta L Vora
• 金额: $ 68.01万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10277107
• 关键词: Ablation; Adult; Affect; Age; Anatomy; Animal Model; Bioinformatics; Biological Models; Brain; CRISPR/Cas technology; Candidate Disease Gene; Child; Clinical; Clinical Data; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Collection; Complex; Congenital Abnormality; Counseling; Coupled; Data; Defect; Development; Diagnosis; Diagnostic; Diagnostic tests; Dideoxy Chain Termination DNA Sequencing; Dissection; Enrollment; Etiology; Family; Fetus; Future; Gene Abnormality; Genes; Genetic; Genetic Diseases; Genomics; Genotype; Healthcare Systems; Heterogeneity; Holoprosencephaly; Human; Hybrids; Image; Infant; Knowledge; Larva; Lead; Lesion; Life; Light; Link; Live Birth; Magnetic Resonance Imaging; Mendelian disorder; Messenger RNA; Modeling; Molecular; Molecular Diagnosis; Morbidity - disease rate; Multiple Abnormalities; Newborn Infant; Operative Surgical Procedures; Orthologous Gene; Parents; Pathogenicity; Phenotype; Physiological; Population; Population Genetics; Prenatal Diagnosis; Prevention strategy; Preventive; Process; Prognosis; Prospective cohort; RNA Splicing; Recurrence; Retrospective cohort; Risk; Site; Structure; Syndrome; Testing; Therapeutic; Traction; Ultrasonography; United States; Variant; Work; Zebrafish; bioinformatics tool; body system; brain abnormalities; cohort; exome; exome sequencing; fetal; fetal diagnosis; gene complementation; gene discovery; genetic analysis; genetic disorder diagnosis; genetic testing; genome editing; genome sequencing; genome-wide; human disease; human model; improved; in utero; in vivo; in vivo Model; knock-down; member; model development; new technology; novel; novel therapeutics; perinatal period; phenotypic data; postnatal; prenatal; proband; prospective; protein function; rare variant; stem; therapeutic target; tool; whole genome; zebrafish genome

ABSTRACT Fetal brain abnormalities (FBA) are one of the most common prenatal sonographic abnormality detected and account for ~20% of birth defects posing a substantial burden on the health care system. FBA can be isolated or syndromic and have vast phenotypic heterogeneity. The paired approach of prenatal diagnosis using ultrasound to characterize aberrant phenotypes with genetic analysis to determine causal lesions has improved the ability to accurately counsel families about diagnosis, prognosis, and recurrence risk. Recently, prenatal exome sequencing (ES) has been applied in cases of lethal or multiple fetal abnormalities to determine a molecular diagnosis that otherwise could not be identified with traditional testing. Our group and others using ES have shown a diagnostic rate of 23.6% in cases of multiple fetal abnormalities, but only 2.6% in isolated FBA abnormalities, indicating a need to improve diagnostic capabilities for FBA. We posit that the overabundance of unresolved fetal cases is due to a gap in our understanding of the repertoire of genotypes underlying prenatal FBA and limitations of population genetics to establish causality of rare variants in novel candidate genes. Our team who is at the forefront of prenatal genetic diagnostics and in vivo zebrafish modeling of human disease will overcome the current challenges of diagnosing prenatal FBA. We will intersect exome- and genome-wide variation with a relevant model system (zebrafish). We hypothesize that we will 1) generate initial discoveries directly relevant to human brain development by modeling novel candidate FBA genes in zebrafish; and 2) improve prenatal diagnosis for FBA using whole genome sequencing (WGS) and deep phenotyping. We will: 1. Perform bioinformatic analysis of 200+ clinically ascertained fetuses with FBA and their parents using a tiered filtering strategy on already available parent-fetus trio exome data 2. Perform WGS on 114 prospectively enrolled fetuses and their parents paired with comprehensive prenatal and postnatal phenotypic data to further characterize genotype/phenotype of FBA; 3. Establish relevance of candidate genes to FBA development and determine variant pathogenicity using genome-editing and phenotyping tools in zebrafish. Our work will expand the understanding of molecular processes governing human brain development, establish a clinical-research hybrid platform readily applicable to FBA and other anatomical defects detectable by fetal imaging, build an animal model of aberrant FBA development with potential for future use in therapeutic target identification. Our immediate results will improve counseling/management of prenatally diagnosed FBA and lead to future work to develop novel therapeutic and preventative strategies for FBA.

抽象的 胎儿脑异常（FBA）是最常见的产前超声检查异常之一 约占出生缺陷的 20%，给医疗保健系统带来沉重负担。 FBA可隔离 或综合征，并且具有巨大的表型异质性。产前诊断的配对方法 超声来表征异常表型并通过遗传分析来确定因果病变已得到改善 能够准确地向家人提供关于诊断、预后和复发风险的建议。最近，产前 外显子组测序 (ES) 已应用于致命性或多发性胎儿畸形的病例，以确定 传统测试无法识别的分子诊断。我们组和其他人使用 ES 多项胎儿异常病例的诊断率为 23.6%，但孤立 FBA 的诊断率为 2.6% 异常，表明需要提高FBA的诊断能力。我们假设过剩 未解决的胎儿病例是由于我们对产前基因型的了解存在差距 FBA 和群体遗传学的局限性，以确定新候选基因中罕见变异的因果关系。我们的 处于产前基因诊断和人类疾病体内斑马鱼模型前沿的团队将 克服当前诊断产前 FBA 的挑战。我们将在外显子组和基因组范围内进行交叉 与相关模型系统（斑马鱼）的变异。 我们假设我们将 1) 产生初步发现 通过对斑马鱼中新的候选 FBA 基因进行建模，与人类大脑发育直接相关；和 2) 使用全基因组测序 (WGS) 和深度表型分析改善 FBA 的产前诊断。我们将： 1. 使用分层方法对 200 多个临床确定的 FBA 胎儿及其父母进行生物信息分析 对已有的亲胎儿三重外显子组数据的过滤策略 2. 对 114 名预期入组的患者进行全基因组测序 (WGS) 胎儿及其父母与全面的产前和产后表型数据配对，以进一步 表征 FBA 的基因型/表型； 3. 建立候选基因与FBA开发的相关性 使用斑马鱼基因组编辑和表型分析工具确定变异致病性。我们的工作将会扩大 了解控制人类大脑发育的分子过程，建立临床研究 混合平台很容易适用于 FBA 和其他可通过胎儿成像检测到的解剖缺陷，建立一个 异常 FBA 发育的动物模型具有未来用于治疗靶标识别的潜力。我们的 立竿见影的结果将改善产前诊断 FBA 的咨询/管理，并导致未来的工作 制定新的 FBA 治疗和预防策略。