Familial frontotemporal dementia: from gene discovery to clinical molecular diagnostics

Genetic testing is important for diagnosis and prediction of many diseases. The development of a clinical genetic test can be rapid for common disorders, but for rare genetic disorders this process can take years, if it occurs at all. We review the path from gene discovery to development of a clinical genetic test, using frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) as an example of a complex, rare genetic condition. An Institutional Review Board-approved multidisciplinary research program was developed to identify patients with familial frontotemporal dementia. Genetic counseling is provided and DNA obtained to identify mutations associated with FTDP-17. In some cases it may be appropriate for individuals to be given the opportunity to learn information from the research study to prevent unnecessary diagnostic studies or the utilization of inappropriate therapies, and to make predictive testing possible. Mutations identified in a research laboratory must be confirmed in a clinical laboratory to be used clinically. To facilitate the development of clinical genetic testing for a rare disorder, it is useful for a research laboratory to partner with a clinical laboratory. Most clinical molecular assays are developed in research laboratories and must be properly validated. We conclude that the transition of genetic testing for rare diseases from the research laboratory to the clinical laboratory requires a validation process that maintains the quality-control elements necessary for genetic testing but is flexible enough to permit testing to be developed for the benefit of patients and families.