Microphthalmia, Anophthalmia, and Coloboma Genetic Epidemiology in Children (MAGIC) Study

儿童小眼症、无眼症和缺损遗传流行病学 (MAGIC) 研究

• 批准号: 10157486
• 负责人: Brian Patrick Brooks
• 金额: $ 76.99万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10157486
• 关键词: 3-Dimensional; Affect; Anophthalmos; Awareness; Birth; Blindness; Brain imaging; Child; Clinical; Clinical Management; Coloboma; Complex; Congenital Abnormality; Consent; Core Facility; Counseling; DNA Sequence Alteration; Defect; Diagnosis; Disease; Disease Surveillance; Echocardiography; Eligibility Determination; Epidemiologist; Epidemiology; Etiology; Evaluation; Eye; Face; Failure; Family; First Degree Relative; Fissural; Genes; Genetic; Genetic study; Genomics; Genotype; Goals; Hearing; Image; Individual; Informed Consent; Interview; Laboratories; Live Birth; Magnetic Resonance Imaging; Malignant Childhood Neoplasm; Medical Records; Microphthalmos; Monitor; National Eye Institute; Neuropsychological Tests; Ocular orbit; Ophthalmic examination and evaluation; Ophthalmologist; Parents; Pathogenicity; Persons; Phenotype; Physical assessment; Population Study; Predisposition; Prevalence; Prevention; Recording of previous events; Registries; Research; Resources; Role; Sampling; Screening for cancer; Series; Syndrome; System; Texas; Time; United States National Institutes of Health; Variant; Vital Status; Work; cancer predisposition; clinical center; cohort; digital imaging; epidemiology study; fetal; gene panel; genetic epidemiology; genetic testing; genetic variant; improved; insight; malformation; member; multidisciplinary; novel; population based; precision medicine; surveillance strategy

ABSTRACT Congenital defects of the eye occur in approximately 5 per 10,000 live births. While there is a paucity of epidemiologic information about these conditions, there is a growing awareness of the long-term complications among children with these malformations. Among the more common visually threatening congenital eye defects are anophthalmia (total absence of the globe); microphthalmia (anomalously small eye in the orbit); and coloboma (failure of the closure of the fetal fissure). Collectively, these defects are referred to as MAC complex and are considered part of an embryologic continuum of ocular malformations. Although MAC accounts for approximately 12% of permanent blindness, epidemiologic studies have provided few insights into the causes of these conditions. While genetic studies have been more fruitful, in clinical series, the known MAC-related genes account for less than half of cases and there are no population-based estimates of the proportion of MAC cases attributable to genetic mutations. Thus, our understanding of the genetics of MAC remains incomplete and there are likely to be additional, as yet, unidentified MAC genes. In addition, there have been few efforts to systematically characterize affected individuals with respect to co-occurring phenotypes (herein termed “deep phenotyping”), which could provide insights into the underlying etiologies of these conditions, define genotype-phenotype correlations, and ultimately inform precision medicine efforts. Our long-term goal is to improve prevention efforts for and clinical management of MAC. The objectives of the current study are to 1) better define the MAC phenotype and 2) characterize the role of known and newly identified pathogenic genetic variants that confer MAC susceptibility. We will leverage the resources of the Texas Birth Defects Registry (TBDR), which is one of the world's largest population-based birth defects surveillance systems that has actively monitored births throughout the state since 1999. Additionally, we will utilize the resources of the National Institutes of Health (NIH) Clinical Center to comprehensively phenotype cases with MAC, and the National Eye Institute (NEI) Ophthalmic Genomics Laboratory to identify genetic variants underlying MAC phenotypes. Our multidisciplinary team of epidemiologists, ophthalmologists, and geneticists has an established track-record in MAC research and is uniquely poised to reach our objectives through completion of the following Aims: 1) Define the phenotypic spectrum of children diagnosed with MAC and determine the prevalence of pathogenic variants in known and suspected MAC-related genes; 2) Conduct deep phenotyping of individuals with MAC and their first-degree relatives; and 3) Discover novel MAC-related genes among individuals without known pathogenic variants. This study will be the first to comprehensively characterize the genotypic and phenotypic spectrum on a population-based sample of children living with MAC. Results from this study will inform genetic testing, counseling, treatment, and disease surveillance strategies for these individuals with MAC.

摘要 每10,000名活产儿中约有5人患有先天性眼睛缺陷。虽然有很少的 关于这些情况的流行病学信息，人们对长期并发症的认识日益增强 在患有这些畸形的儿童中。在更常见的视觉威胁先天性眼睛中 缺陷是无眼球(完全没有眼球)；小眼球(眼眶内异常小的眼睛)； 和缺陷症(胎儿裂隙关闭失败)。这些缺陷统称为MAC 复杂，被认为是眼畸形胚胎连续体的一部分。尽管MAC 约占永久性失明的12%，流行病学研究几乎没有提供对 这些情况的原因。虽然遗传学研究已经取得了更多的成果，但在临床系列中，已知的 Mac相关基因占病例的不到一半，而且没有基于人群的估计 可归因于基因突变的MAC病例比例。因此，我们对MAC的遗传学的理解 仍然是不完整的，很可能还有其他尚未确定的MAC基因。此外，还有 几乎没有努力系统地描述受影响的个体的共生情况 表型(这里称为“深层表型”)，这可以提供对潜在的病因的洞察 这些条件，定义了基因-表型的相关性，并最终为精确医学的努力提供了信息。我们的 长期目标是改善对MAC的预防和临床管理。该计划的目标 目前的研究是为了1)更好地定义MAC表型和2)表征已知的和新的 确定了导致MAC易感性的致病遗传变异。我们将利用 德克萨斯州出生缺陷登记处(TBDR)，这是世界上最大的以人口为基础的出生缺陷之一 自1999年以来一直在全州积极监测出生情况的监测系统。此外，我们还将 利用美国国立卫生研究院(NIH)临床中心的资源，综合表型 患有MAC的病例，与美国国家眼科研究所(NEI)眼科基因组实验室鉴定基因 MAC表型的潜在变异。我们由流行病学家、眼科医生和 遗传学家在MAC研究方面有既定的记录，并独一无二地准备实现我们的目标 通过完成以下目标：1)确定被诊断为MAC的儿童的表型谱 并确定已知和可疑的MAC相关基因中致病变异的流行率；2)进行 MAC患者及其一级亲属的深入表型；以及3)发现与MAC相关的新基因 没有已知致病变异的个体之间的基因。这项研究将是第一个全面 以人群为基础的儿童MAC患者样本的基因型谱和表型谱特征。 这项研究的结果将为基因测试、咨询、治疗和疾病监测策略提供参考 对于这些患有MAC的人来说。