Rationale:Taking findings from basic research to practical applications that enhance human health and well-being is the signification of translational research. Improvement in human health and well-being, however, does not necessarily involve the cure of a disease. Sometimes mere information transfer might help patients substantially in dealing with their medical condition. This is particularly true for patients with family history of yet unknown or contradictory diagnoses – in other words for patients with rare hereditary diseases. This point was emphasized very recently by Erika C. Hayden in Nature . Providing information is the foundation of molecular genetic diagnostics and genetic counseling, which should readily be available for any inherited disease, even if no cure will be available in the foreseeable future. The provided information can answer basic questions of the patient, such as What do I have? Why my family? Is there a risk for my children? Is there anything I can do about it? And this will assist the patient in understanding their medical condition.
COL4A1 (OMIM: *120130) and COL4A2 (OMIM: *12090) encode for extra cellular matrix proteins that constitute basement membranes. Mutations in COL4A1 and COL4A2 cause multi–system disorders including porencephaly, cerebral small vessel disease with hemorrhage, Axenfeld-Rieger anomaly with glaucoma, and variable muscular dystrophy including muscle-eye-brain disease. To date, more than 50 different pathogenic sequence variances have been described in highly penetrant multi-system disorders. For ICH – the only disease so far that has been systematically screened for COL4A1 and COL4A2 sequence variants – we estimate that mutations in COL4A1 and COL4A2 may cause up to 10% of all cases of spontaneous ICH. The Gould lab identified the first COL4A1 mutations in mice and humans and recently published a comprehensive review on the topic. For these and other reasons, the Gould lab receives inquiries from researchers, clinicians and patients throughout the world interested in collaborations, clinical advice or participation in research. We recognize that many other labs at UCSF and around the world face these same types of requests. We propose that developing a centralized information management system (IMS) to promote and streamline interactions and communication between these three stakeholders will be an efficient and effective paradigm to enhance translational research.
Based up on the platform developed by the Leiden Open Variation Database (LOVD) we will generate a centralized information management system (IMS) that streamlines interchange of information between patients, clinicians, and researchers. The IMS will be tripartite in order to provide the relevant information to the appropriate target audience. We will develop the platform using COL4A1 and COL4A2 as a scalable model for any number of other groups.
- Patients will find a comprehensive overview on the different disorders associated with COL4A1 and COL4A2, as well as a platform to connect to medical doctors, researchers, and genetic counselors especially trained on these medical conditions.
- Medical doctors and genetic counselors will find a locus-specific database that collects all sequence variations in COL4A1 and COL4A2 with links to the according reference of their initial description, the latest literature on COL4A1 and COL4A2, as well as information on ongoing patient studies.
- Researchers will maintain the IMS and thereby find a useful research dataset for molecular diagnosis, large-scale mutation statistics, and the determination of genotype-phenotype correlations. Research will also benefit from a collaborations platform, which promotes discussion in the field. They will also identify patients willing to donate biological material for further investigations on multi-system disorders.
Criteria and Metrics for Success:
- Set-up a locus-specific database for COL4A1 and COL4A2 based on the format used for the Leiden Open Variation Database (June 1, 2013).
- Set-up a literature database on COL4A1 and COL4A2 based on the Mendeley open source reference manager (June 1, 2013).
- Write a comprehensive overview on the different disorders associated withCOL4A1 and COL4A2 and update all according NCBI datasets (July 1, 2013).
- Collect information on MDs and genetic counselors that are especially trained on medical conditions associated with COL4A1 and COL4A2 based on information provided by experts and databases, such as GeneTests(July 1, 2013).
- Create an interactive web-interface that links all the different resources by July 1, 2013.
- Go live by August 1, 2013.
- This IMS will increase clinicians’ awareness of COL4A1 and COL4A2 as one possible cause for multi-system disorders and they will find necessary resources and information to help make decisions for their patients.
- Interested patients with multi-system disorders can arrange to donate biological samples, such as DNA or skin biopsies, to researchers listed on the IMS in order to promote research on multi-system disorders.
- The IMS can be a model for other inherited diseases and may lay the seed for an extended IMS that comprises also other genes and diseases.
- Once the platform is established we will use it as the model and continue to build this resource for other inherited diseases of the extracellular matrix.
- Establish this platform as a template for other UCSF researchers and clinicians to interface with each other and with patients to promote information transfer and patient recruitment.
- In summary, this proposal will improve the conduct of research on a devastating disease here at UCSF and worldwide.
Total Budget: $22,000
Summer student: $4000/mo for 3 months = $12,000
Web Developer: $50/hr for 1 month = $8,000
Postdoctoral Fellow to oversee project 15% effort for 3 months = $2,000
1. Hayden EC: Data barriers limit genetic diagnosis. Nature 2013, 494(7436):156-157.
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