SUMMARY This supplemental application for the BCM and U of Oregon MOSC proposes to continue to study and characterize variants in genes that have been submitted by the clinical sites of the UDN during phase II as well as anticipated new submissions in the coming year. We need to ensure that all patients that have been accepted by the clinical sites are treated equally and have a fair chance of being diagnosed. Hence, we will continue ongoing experiments on 32 genes in the fly MOSC and 12 genes in the fish MOSC submitted in phase I and II. We have already gathered data that suggest that many of these variants may be causative and the goal is now to obtain more compelling evidence that they are indeed the cause of disease and to publish the data in collaboration with the UDN sites. Based on previous experience, numerous cases are being diagnosed world-wide after we publish our work and well over 200 patients with rare diseases have benefited from our publications. Completing ongoing cases and anticipated new cases will require a very significant amount of resources and work at both sites. The work is so substantial that requested resources will need to be complemented with funding from private donors as well as institutional support. Given the considerable documented time lag between sequencing and submission to the MOSCs, we anticipate that many cases that will be submitted in the next year by the clinical sites will be cases that were accepted in phase I and II. We will accept many of these cases if we think we can model them in a timely fashion, even if this will exceed the funding period and we will therefore seek support from other sources