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

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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.