Dissecting ocular congenital cranial dysinnervation disorders through whole genome sequence analysis

通过全基因组序列分析剖析眼部先天性颅神经失调性疾病

• 批准号: 10222695
• 负责人: Elizabeth C. Engle
• 金额: $ 55.76万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222695
• 关键词: Affect; Animal Model; Area; Axon; Beds; Biology; Candidate Disease Gene; Categories; Cell model; Cells; Cephalic; Clinical; Code; Complex; Computer software; Congenital Abnormality; Congenital neurologic anomalies; Copy Number Polymorphism; Cranial Nerves; Critical Pathways; DNA Sequence; Data; Data Analyses; Data Set; Databases; Detection; Development; Disease; Etiology; Eye; Eyelid structure; Family; Family member; Functional disorder; Funding; Genes; Genetic; Genetic Counseling; Genetic Enhancement; Genetic Predisposition to Disease; Genome; Genomics; Genotype; Goals; Grant; Health; Human; In Vitro; Individual; Infant; Informatics; Institutes; International; Interpersonal Relations; Lead; Mendelian disorder; Methods; Modeling; Motor Neurons; Movement; Movement Disorders; Mus; Mutation; Neurons; Organ; Other Genetics; Paralysed; Pathogenicity; Patients; Pediatric Research; Phenotype; Process; Rare Diseases; Rest; Sampling; Secondary to; Sequence Analysis; Single Nucleotide Polymorphism; Structural Congenital Anomalies; Structure; Syndrome; Testing; Translating; United States National Institutes of Health; Untranslated RNA; Validation; Variant; Visual impairment; Work; causal variant; cohort; computerized data processing; de novo mutation; disability; exome sequencing; genetic approach; genetic disorder diagnosis; genetic pedigree; human disease; human embryonic stem cell; improved; in vitro Assay; in vivo; insertion/deletion mutation; large datasets; mouse model; nerve supply; novel; novel strategies; oculomotor; open source; orbit muscle; proband; programs; self esteem; success; targeted sequencing; whole genome

PROJECT SUMMARY (ABSTRACT) The goals of this proposal are to identify novel genetic causes of ocular `congenital cranial dysinnervation disorders' (CCDDs) thorough analysis of whole genome sequence (WGS) data and to define the phenotype- genotype correlations and neurodevelopmental mechanisms underlying these newly identified CCDD disease genes. It is estimated that more than 1 of every 1000 infants is born with the inability to move one or both eyes in one or more directions. Such disorders cause significant disability and are frequently accompanied by additional structural birth defects, and often segregate within families or arise from de novo mutations. MPI Engle's genetic and developmental studies have led to the definition of these syndromes as a new category of human disease. Her lab has defined multiple CCDD syndromes, uncovered their genetic etiologies, and, through modeling in model organisms, determined that these disorders can result from maldevelopment of cranial motor neurons and their axonal processes. Despite these successes, over 80% of the Engle Lab ocular CCDD cohort remains genetically unsolved. To identify new ocular CCDD genes, MPI Engle has been granted WGS of DNA samples from genetically undefined CCDD probands and family members through the Gabriella Miller Kids First Pediatric Research Program. Analysis of WGS will allow detection of non-coding variants, copy number variations, and complex structural rearrangements, while also providing better coverage of coding regions than exome sequencing, thus filling several critical gaps missed by other genetic approaches such as exome sequencing. MPI MacArthur is an international leader in the genomic analysis of large datasets in the context of rare disease. His team will analyze the WGS from >700 individuals and family members with ocular CCDDs, provide rigorous data processing, and work closely with MPI Engle's team to evaluate evidence supporting variant pathogenicity. Critically, the involvement of MPI MacArthur will allow us to analyze our samples in the context of over 20,000 control genomes sequenced at the Broad Institute, as well as additional structural birth defect genomes generated by the Kids First consortium. Together with targeted sequencing of additional probands in the Engle CCDD database, this harmonization will enhance our power to determine pathogenicity and phenotype-genotype correlations. Employing the functional approaches established in MPI Engle's lab to study the neurodevelopmental and mechanistic etiologies of ocular CCDDs, high-confidence novel disease genes will be moved to functional studies in vitro and in vivo. Thus, we expect that analysis of this unique patient cohort will lead to the identification of missing monogenic causes of CCDDs and that validation, replication, and functional studies will elucidate new genetic and developmental pathways critical to ocular cranial nerve development. In turn, this will enhance genetic diagnoses and counseling in patients and families with ocular CCDDs, inform motor neuron and axon development in health and disease, and contribute to improved therapies and reduced disabilities that arise secondary to these Mendelian disorders.

项目概要（摘要） 该提案的目标是确定眼部“先天性颅神经失调”的新遗传原因 疾病'（CCDD）对全基因组序列（WGS）数据进行彻底分析并定义表型- 这些新发现的 CCDD 疾病背后的基因型相关性和神经发育机制 基因。据估计，每 1000 名婴儿中就有超过 1 名出生时一只或双眼无法转动 朝一个或多个方向。此类疾病会导致严重的残疾，并经常伴有 其他结构性出生缺陷，通常在家庭内分离或由新生突变引起。 MPI 恩格尔的遗传和发育研究将这些综合征定义为一个新的类别 人类疾病。她的实验室定义了多种 CCDD 综合征，揭示了它们的遗传病因，并且， 通过模型生物建模，确定这些疾病可能是由发育不良引起的 颅运动神经元及其轴突。尽管取得了这些成功，超过 80% 的 Engle Lab 目镜 CCDD 队列在遗传学上仍未得到解决。为了鉴定新的眼部 CCDD 基因，MPI Engle 已获得授权 通过 Gabriella 对基因未定义的 CCDD 先证者和家庭成员的 DNA 样本进行全基因组测序 (WGS) 米勒儿童第一个儿科研究计划。 WGS 分析将允许检测非编码变异、复制 数字变化和复杂的结构重新排列，同时还提供更好的编码覆盖范围 区域比外显子组测序，从而填补了其他遗传方法遗漏的几个关键空白，例如 外显子组测序。 MPI MacArthur 是大型数据集基因组分析领域的国际领导者 罕见疾病的背景。他的团队将使用目视分析来自超过 700 名个人和家庭成员的 WGS CCDD，提供严格的数据处理，并与 MPI Engle 的团队密切合作来评估证据 支持变异致病性。至关重要的是，MPI MacArthur 的参与将使我们能够分析我们的 在布罗德研究所测序的 20,000 多个对照基因组背景下的样本，以及其他 由 Kids First 联盟生成的结构性出生缺陷基因组。连同靶向测序 Engle CCDD 数据库中的其他先证者，这种协调将增强我们确定的能力 致病性和表型-基因型相关性。采用 MPI 中建立的功能方法 恩格尔实验室研究眼部 CCDD 的神经发育和机制病因学，高可信度 新的疾病基因将被转移到体外和体内的功能研究。因此，我们期望分析 这个独特的患者队列将导致识别 CCDD 缺失的单基因原因，并且 验证、复制和功能研究将阐明新的遗传和发育途径，这对 眼脑神经发育。反过来，这将加强对患者和患者的遗传诊断和咨询。 患有眼部 CCDD 的家庭，了解健康和疾病中运动神经元和轴突的发育，并做出贡献 改善治疗并减少继发于这些孟德尔疾病的残疾。