The eye in rasopathies- phenotypic variation and possible role of modifiers

S.P. Shankar1, D. Orel-Bixler2, T.L. Young3,  K.A. Rauen4

1). Department of Human Genetics and Ophthalmology, Emory University, Atlanta, GA  2). Berkeley Optometry, University of California, Berkeley, CA  3). Center for Human Genetics and Ophthalmology, Duke University, Durham, NC  4). Medical Genetics, University of California San Francisco, San Francisco, CA

The role of the Ras/MAPK signaling in eye and vision development is being increasingly studied and shown to be important in, in-vitro studies, animal models including zebra fish and mouse models and in individuals having rasopathies.

We studied 58 individuals including 28 with Cardiofaciocutaneous (CFC), 16 with Costello syndrome and 14 with Noonan syndrome during Berkeley Ras/MAPK symposium. Additionally we had collected visual exam reports from individuals not in this study. Both similarities and differences in the ocular presentation were noted in all three syndromes.  The most serious visually disabling problem not amenable to treatment currently was optic nerve hypoplasia. However, not all individuals had optic nerve involvement. About 30% of CFC, 10-20% of Costello children and 10-20% of Noonan individuals have optic nerve involvement.

Most individuals had either or frequently both 1).ocular alignment problems  resulting in strabismus– exotropia (an eye or eyes turning outward), esotropia (inward crossing of the eyes), hypertropia (one eye being higher than the other) and 2). refractive errors including myopia (near-sightedness), hyperopia (far-sightedness) and astigmatism. These issues commonly resulted in problems with depth perception, abnormal head posturing and amblyopia (diminished visual acuity due to unequal eye use). Functional studies showed that most individuals had reasonably good vision in one or both eyes, but lacked depth perception. Some other issues included nystagmus (rhythmic shaking of the eyes) and ptosis (droopy eye-lids).

Even though all of these individuals have disruption of the Ras/MAPK pathway, there is a wide range of phenotype variation.  A good example is Costello syndrome, caused by missense mutations in the gene HRAS, with the Gly12Ser substitution accounting for >80% of all individuals with a known mutation with only few individuals having optic nerve hypoplasia.  This suggests the role for modifier genes or environmental factors predisposing one individual to develop optic nerve hypoplasia or alternatively protecting another from developing it. If we are able to understand these factors better it would help not only the individuals with CFC, Costello and Noonan but may also help in developing therapeutic options for optic nerve hypoplasia in general population.

We propose to do genotype-phenotype correlation studies in affected individuals and also study ocular phenotype in animal models to better understand the pathogenic mechanisms contributing to these eye development disorders.

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