) The goals of this proposal are to identify novel genetic causes of ocular `congenital cranial dysinnervation disorders' (CCDDs) thorough analysis of whole genome sequence (WGS) data and to define the phenotype- genotype correlations and neurodevelopmental mechanisms underlying these newly identified CCDD disease genes. It is estimated that more than 1 of every 1000 infants is born with the inability to move one or both eyes in one or more directions. Such disorders cause significant disability and are frequently accompanied by additional structural birth defects, and often segregate within families or arise from de novo mutations. MPI Engle's genetic and developmental studies have led to the definition of these syndromes as a new category of human disease. Her lab has defined multiple CCDD syndromes, uncovered their genetic etiologies, and, through modeling in model organisms, determined that these disorders can result from maldevelopment of cranial motor neurons and their axonal processes. Despite these successes, over 80% of the Engle Lab ocular CCDD cohort remains genetically unsolved. To identify new ocular CCDD genes, MPI Engle has been granted WGS of DNA samples from genetically undefined CCDD probands and family members through the Gabriella Miller Kids First Pediatric Research Program. Analysis of WGS will allow detection of non-coding variants, copy number variations, and complex structural rearrangements, while also providing better coverage of coding regions than exome sequencing, thus filling several critical gaps missed by other genetic approaches such as exome sequencing. MPI MacArthur is an international leader in the genomic analysis of large datasets in the context of rare disease. His team will analyze the WGS from >700 individuals and family members with ocular CCDDs, provide rigorous data processing, and work closely with MPI Engle's team to evaluate evidence supporting variant pathogenicity. Critically, the involvement of MPI MacArthur will allow us to analyze our samples in the context of over 20,000 control genomes sequenced at the Broad Institute, as well as additional structural birth defect genomes generated by the Kids First consortium. Together with targeted sequencing of additional probands in the Engle CCDD database, this harmonization will enhance our power to determine pathogenicity and phenotype-genotype correlations. Employing the functional approaches established in MPI Engle's lab to study the neurodevelopmental and mechanistic etiologies of ocular CCDDs, high-confidence novel disease genes will be moved to functional studies in vitro and in vivo. Thus, we expect that analysis of this unique patient cohort will lead to the identification of missing monogenic causes of CCDDs and that validation, replication, and functional studies will elucidate new genetic and developmental pathways critical to ocular cranial nerve development. In turn, this will enhance genetic diagnoses and counseling in patients and families with ocular CCDDs, inform motor neuron and axon development in health and disease, and contribute to improved therapies and reduced disabilities that arise secondary to these Mendelian disorders.
(RELEVANCE) Congenital paralysis of eye and eyelid movements results in impaired vision and is often accompanied by additional anomalies of the nervous system and other organs. Moreover, eye and lid movement disorders can profoundly disturb interpersonal interactions and self-esteem. The MPIs will analyze whole genome sequence data from over 700 individuals from families affected with these disorders to identify new disease genes and to study how these new genes alter development in humans and in cell and animal models.
| Dobyns, William B; Aldinger, Kimberly A; Ishak, Gisele E et al. (2018) MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance. Am J Hum Genet 103:1009-1021 |
| Di Gioia, Silvio Alessandro; Shaaban, Sherin; Tüysüz, Beyhan et al. (2018) Recessive MYF5 Mutations Cause External Ophthalmoplegia, Rib, and Vertebral Anomalies. Am J Hum Genet 103:115-124 |
| Shaaban, Sherin; MacKinnon, Sarah; Andrews, Caroline et al. (2018) Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect. Invest Ophthalmol Vis Sci 59:4054-4064 |
