New quality assurance standards for rare disease testing.

A primary tenet in the field of laboratory medicine is that research and clinical service activities should be kept separate both physically and operationally. This is because the quality assurance, record-keeping, and personnel requirements for clinical laboratory testing are very stringent, mandatory, and inflexible. Such conditions are deemed appropriate and necessary for assuring consistency, timeliness, and reliability of high-complexity assays directly affecting patient care, not to mention the potential for loss of laboratory accreditation associated with lax adherence and the risk of liability from resulting errors. On the other hand, such dogmatic and regimented attention to detail may be counterproductive for the research setting which thrives on inventiveness, imagination, and pliancy. The field of molecular diagnostics, by its very nature, has always represented a marriage of research advances translated into clinical applications. Clinical molecular genetics laboratories often work in close concert with basic molecular genetics research laboratories, and many molecular diagnostic laboratory directors are heavily involved in basic research themselves. As such, we have been especially cognizant of this need for separation and the difficulty we sometimes face in doing so. There is one area of molecular genetic testing that is particularly caught in the middle ground between research and service: the detection of mutations in genes for ultra-rare disorders. Ultra-rare disorders have been defined in this guidance document as having a prevalence of less than 2000 affected individuals in the US population, although no formal statutory definition exists. Ultra-rare disorders are considered less common than rare disorders. Rare disorders have been defined by the Orphan Drug Act of 1983 as those that affect less than 200,000 individuals in the United States. Some examples include pantothenate kinase-associated neurodegeneration, infantile neuroaxonal dystrophy syndrome, and X-linked ocular albinism. Because of their rarity, test request volume is generally too low to be of interest to mainstream clinical molecular genetics laboratories, whether in the academic or commercial setting. Moreover, the involved genes are often studied by only one or a few researchers, and they are the only ones with the reagents, knowledge, and experience to perform the tests. This state of affairs is not surprising when one considers the typical evolution of genetic disease discovery. This typical chronology begins with the encounter by an interested clinical investigator of one or more patients with a particular genetic disease. Specimens (usually blood) are collected from these patients for diagnostic (e.g., biochemical) testing and disease characterization. At the same time, genomic DNA is isolated, and if sufficiently large families or numbers of families can be accrued, gene mapping studies by linkage analysis are commenced. With luck, the causative gene will be discovered and published. Often the very next publication from the laboratory describes a mutation survey of the sequence changes in all the patients whose DNA has been collected and stored. But in most cases these studies are not especially exciting or revealing, comprised predominantly of routine missense and nonsense variants that do not shed much light on the molecular mechanisms of the disease or the gene product. Naturally, the research laboratory would then prefer to move on to these more functional studies, but because the investigators may be the only ones in the world set up to do the mutation detection assay, the families keep returning to them with requests for carrier testing and prenatal diagnosis. Sometimes researchers are put under pressure by their own institutional review boards to reveal test results to study participants, but this simply reflects misunderstanding of the law (see below). Usually the researchers will accede to these requests, either out of altruism or a feeling of indebtedness to the families who assisted in the gene mapping. But because this is no longer a high priority activity of the laboratory, such requests are often assigned to lesser qualified members of the team (e.g., junior graduate students) or otherwise put on the back burner, leading to poor turnaround time and analytic or clerical errors. Clearly, this situation is far from ideal and does not serve well either the patients or the researchers. And even beyond that, there are legal issues at hand. The Clinical Laboratory Improvement Amendments (CLIA) mandate that only a licensed clinical laboratory can issue test results to physicians or patients that will be used for medical management. Because the research laboratory does not have a CLIA license (or any other clinical certification), it is technically in violation of federal law every time it gives out a test result. Although the law is usually not enforced in a punitive way, especially for rare diseases where a “compassionate use” concern may override the legal concerns (just as for orphan drugs), it is not in anyone’s best interest for the status quo to be perpetuated indefinitely. Still, Departments of Pathology and Laboratory Medicine, Pediatrics, and Human Genetics, UCLA School of Medicine, Los Angeles, California; and Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon.