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: 10397056
• 负责人: Brian Patrick Brooks
• 金额: $ 73.25万
• 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/10397056
• 关键词: 3-Dimensional; Affect; Anophthalmos; Awareness; Birth; Blindness; 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; 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; brain magnetic resonance imaging; 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名活产婴儿中约有5人患有先天性眼部缺陷。虽然缺乏 随着有关这些疾病的流行病学信息的增加，人们对长期并发症的认识越来越高 有这些畸形的儿童。在较常见的威胁视力的先天性眼睛 缺陷是无眼症（完全没有地球仪）、小眼症（眼眶中的小眼睛）; 和缺损（胎儿裂隙闭合失败）。这些缺陷统称为MAC 复杂，被认为是眼部畸形的胚胎连续体的一部分。虽然MAC 约占永久性失明的12%，流行病学研究几乎没有提供关于 这些情况的原因。虽然遗传学研究已经取得了更丰硕的成果，但在临床系列中，已知的 MAC相关基因占不到一半的病例，并且没有基于人群的估计。 MAC病例的比例可归因于基因突变。因此，我们对MAC遗传学的理解 仍然是不完整的，很可能有额外的，迄今为止，身份不明的MAC基因。此外还有 很少有人努力系统地描述受影响的个人与共同发生的 表型（本文称为“深度表型”），这可以提供对潜在病因学的见解， 这些条件定义了基因型-表型相关性，并最终为精确医学的努力提供了信息。我们 长期目标是改善MAC的预防工作和临床管理。的目标 目前的研究是1）更好地定义MAC表型和2）表征已知和新的作用， 鉴定了赋予MAC易感性的致病性遗传变异。我们将充分利用 德克萨斯州出生缺陷登记处（TBDR），这是世界上最大的基于人口的出生缺陷之一 自1999年以来一直积极监测全州出生情况的监测系统。此外，我们将 利用美国国立卫生研究院（NIH）临床中心的资源， 病例MAC，和国家眼科研究所（NEI）眼科基因组学实验室，以确定遗传 MAC表型的潜在变异。我们的流行病学家，眼科医生， 遗传学家在MAC研究方面有着良好的记录，并且能够实现我们的目标 通过完成以下目标：1）确定诊断为MAC的儿童的表型谱 并确定已知和疑似MAC相关基因中致病变异的患病率; 2）进行 对MAC患者及其一级亲属进行深入的表型分析;以及3）发现新的MAC相关 在没有已知致病变异的个体中的基因。这项研究将是第一个全面 描述MAC儿童人群样本的基因型和表型谱。 这项研究的结果将为基因检测、咨询、治疗和疾病监测策略提供信息 这些人与MAC。