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: 10468233
• 负责人: Neeta L Vora
• 金额: $ 65.78万
• 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/10468233
• 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; United States; Variant; Work; Zebrafish; bioinformatics tool; body system; brain abnormalities; cohort; diagnostic tool; diagnostic value; 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; ultrasound; 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）是检测到的最常见的产前超声检查异常之一 约20％的出生缺陷对医疗保健系统造成了重大负担。 FBA可以隔离 或综合征，具有广泛的表型异质性。使用的配对方法使用 超声以通过遗传分析来表征异常表型以确定因果病变已改善 准确地咨询家庭诊断，预后和复发风险的能力。最近，产前 在致命或多种胎儿异常的情况下已应用外显子组测序（ES）来确定A 传统测试无法识别的分子诊断。我们的小组和其他人使用ES 在多种胎儿异常的情况下，诊断率为23.6％，但在孤立的FBA中只有2.6％ 异常，表明需要提高FBA的诊断能力。我们认为 未解决的胎儿病例是由于我们对产前基因型曲目的理解差距 FBA和种群遗传学的局限性在新型候选基因中建立稀有变异的因果关系。我们的 在产前遗传诊断和体内斑马鱼模型的最前沿的团队将 克服当前诊断产前FBA的挑战。我们将与全基因组和全基因组相交 使用相关模型系统（斑马鱼）的变化。 我们假设我们将1）生成初始发现 通过对斑马鱼中的新型候选FBA基因进行建模，与人脑发育直接相关；和2） 使用整个基因组测序（WGS）和深层表型改善产前诊断FBA。我们将：1。 对200多个临床确定的胎儿对FBA及其父母进行生物信息学分析使用分层 对已经可用的父型三人组三人组数据2进行过滤策略2。 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开发的相关性和 使用斑马鱼中的基因组编辑和表型工具确定变异致病性。我们的工作将扩大 对管理人脑发育的分子过程的理解，建立临床研究 混合平台容易适用于FBA和其他可以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，具有未来在治疗靶标识别中使用的可能性。我们的 直接的结果将改善预诊断的FBA的咨询/管理，并导致未来的工作 为FBA制定新颖的治疗和预防策略。