Towards the identification of causal genes and contributing molecular processes underlying strabismus

Eye misalignment, or strabismus, has a frequency of up to 4% in a population, and is known to have both environmental and genetic causes. Genes associated with syndromic forms of strabismus (i.e. strabismus concurrent with multiple phenotypes) have emerged, but genes contributing to isolated strabismus remain to be discovered. Only one isolated strabismus locus, STBMS1 on chromosome 7, has been confirmed in more than one family, but the inheritance model of the locus is inconsistent between studied families and no specific causal variant has been reported. The large set of syndromes with strabismus suggests that within the visual system multiple perturbations of an underlying genetic network(s) can have the common output of disrupted eye alignment. Thus, I used a bioinformatic-driven approach to analyze curated genes associated with strabismus to provide insight into the biological mechanisms underlying strabismus, highlighting a link to the Ras-MAPK pathway. During the process, I noticed strabismus presenting within a large number of intellectual disability disorders. Therefore, I studied the co-occurrence of strabismus and other common phenotypes in a series of patients with intellectual disability, which confirmed a significant correlation between eye alignment and intellectual disability. Finally, I resumed efforts from my prior studies to identify the genetic cause in a seven-generation family with isolated strabismus inherited in an autosomal dominant manner. The likely casual gene disruption, altering a likely cis-regulatory region of the FOXG1gene, was identified through the incorporation of linkage analysis, next generation sequencing, and in-depth bioinformatic analyses. This thesis identifies potential roles for genes participating in the Ras-MAPK pathway, emphasizes the role of the central nervous system, and reveals FOXG1 as a causal gene candidate for isolated strabismus.Medicine, Faculty ofMedical Genetics, Department ofGraduat