Genetic Etiologies of Horizontal Strabismus

Congenital strabismus is the pathological misalignment of the eyes associated with loss of binocular vision. It affects up to 4% of the population worldwide and 6-12 million people in the United States, and can reduce vision in one or both eyes, impair depth perception, and disturb interpersonal interactions and self-esteem. Congenital strabismus may be differentiated into comitant and incomitant forms. Incomitant forms account for 2% of cases, and affected individuals have limited eye movements such that the angle varies with gaze direction. Comitant congenital strabismus (CCS) accounts for 98% of cases, and affected individuals have full eye movements, with the angle of misalignment remaining constant with changes in gaze direction. It includes diagnoses such as esotropia, exotropia, and monofixation syndrome. Genetic and neurodevelopmental studies of rare forms of incomitant strabismus have revealed that it can result from mutations in genes critical to ocular cranial motor neuron development and to the proper growth and guidance of developing axons. In contrast, despite its high incidence, significant morbidity, and high cost to society in lost productivity, the underlying genetic contributors to CCS remain a mystery. Population, family-based, and twin studies all support a strong genetic contribution to CCS, with the relative risk to a first-degree relative of a proband estimated to be between 3 and 5. CCS is well suited for family-based analysis because of its early age of onset, high rate of family recurrence, and ease of family members' recruitment. Thus, the current proposal aims to utilize the existing infrastructure and multidisciplinary team to: (1) Expand ascertainment and phenotypic analysis of CCS for both clinical and genetic studies; (2) Acquire and curate genome-wide genotype data of CCS; (3) Identify rare genetic variants underlying CCS through genome-wide homozygosity mapping and linkage analysis; and (4) Identify common variants contributing to esotropia through genome-wide association study (GWAS). An improved understanding of the genetic etiologies of CCS should provide insight into its neuro-developmental basis and could have a profoundly positive impact on the health and well being of the population. Identification of patients or families at highest risk will improve the efficiency of screening programs, allowing for earlier detection and treatment. The response of individual patients to surgical intervention might be predicted with more accuracy and the surgical outcomes improved if their specific genetic etiology is understood. Finally, understanding the genetics of CCS may inspire the implementation of innovative nonsurgical therapies.