New quality assurance standards for rare disease testing

ArticleinGenetics in medicine: official journal of the American College of Medical Genetics 10(5):320-4 · June 2008with7 Reads
DOI: 10.1097/GIM.0b013e31817283ba · Source: PubMed
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 beginswiththeencounterbyaninterestedclinicalinvestigator of one or more patients with a particular genetic disease. Spec- imens (usually blood) are collected from these patients for di- agnostic (e.g., biochemical) testing and disease characteriza- tion. At the same time, genomic DNA is isolated, and if sufficiently large families or numbers of families can be ac- crued, gene mapping studies by linkage analysis are com- menced. With luck, the causative gene will be discovered and published.Oftentheverynextpublicationfromthelaboratory describes a mutation survey of the sequence changes in all the patientswhoseDNAhasbeencollectedandstored.Butinmost casesthesestudiesarenotespeciallyexcitingorrevealing,com- prised predominantly of routine missense and nonsense vari- antsthatdonotshedmuchlightonthemolecularmechanisms of the disease or the gene product. Naturally, the research lab-
    • "Thus, although the testing may be of high quality, there is no requirement that the safeguards outlined in the CLIA regulation are followed. It is the spirit of the CLIA regulation that results of genetic testing produced in a research laboratory are not to be released to the referring physician to be placed in patient records for use in the diagnosis, therapy, or management of a patient, and the research laboratory is technically in violation of the federal law every time it issues a test result [Grody and Richards, 2008]. Turn-around times may be long (months to years, in many cases) and generally neither the participating patient nor the physician who may have referred the patient to the study will receive a written report of the patient's genetic test results, although a summary of study results for all participating patients may be released. "
    [Show abstract] [Hide abstract] ABSTRACT: "Ectodermal Dysplasia syndromes" comprise a diverse group of heritable conditions characterized by congenital anomalies of one or more ectodermal structures and their appendages: hair, teeth, nails, and sweat glands. Genetic testing is available for many types of ectodermal dysplasia (ED) through clinical and/or research laboratories. We address the distinctions between genetic testing as performed on a clinical versus research basis, and summarize the clinical aspects, testing methodology, and sensitivity for those ED syndromes for which testing is available in a clinical laboratory. Lastly, we leave the laboratory for the clinical setting to discuss the utility of genetic testing for patients and their families, and summarize the practical issues involved in ordering a genetic test.
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  • [Show abstract] [Hide abstract] ABSTRACT: Since 1994, at least three national advisory committees have addressed issues involving access to high-quality genetic testing for ultra-rare genetic diseases. These included the Institute of Medicine (1994), a National Institutes of Health-Department of Energy Task Force on Genetic Testing (1997), and the Secretary's Advisory Committee on Genetic Testing (2000). All identified the limited availability of high-quality testing for these rare diseases as a very high priority and a number of recommendations to improve access were made. However, little systematic progress was made as a direct result of these committee recommendations. Beginning in 2004, a series of national workshops on "Quality Laboratory Testing for Rare Diseases" was organized by a group of clinical laboratory directors experienced in rare disease testing working with the Centers for Disease Control and the Office of Rare Diseases at National Institutes of Health. These meetings included broad-based community involvement, with stakeholders from appropriate federal agencies, professional societies, patient advocacy groups as well as clinical geneticists and clinical genetics laboratory experts. Two successful outcomes of these workshops were the formation of a National Laboratory Network for Rare Disease Testing and a National Institutes of Health-funded program to aid in the translation of new genetic tests from research laboratories to Clinical Laboratory Improvement Amendments-certified diagnostic laboratories known as the Collaboration and Education in Test Translation program. This article briefly reviews the history and current status of genetic testing for ultra-rare genetic diseases in the United States, with a primary focus on molecular genetic testing by DNA sequencing. Other articles in this series provide more detailed reports on the significant progress in improving access to quality genetic testing for rare diseases within the last few years.
    Full-text · Article · Jun 2008
  • [Show abstract] [Hide abstract] ABSTRACT: The speed, accuracy, efficiency, and cost-effectiveness of DNA sequencing have been improving continuously since the initial derivation of the technique in the mid-1970s. With the advent of massively parallel sequencing technologies, DNA sequencing costs have been dramatically reduced. No longer is it unthinkable to sequence hundreds or even thousands of genes in a single individual with a suspected genetic disease or complex disease predisposition. Along with the benefits offered by these technologies come a number of challenges that must be addressed before wide-scale sequencing becomes accepted medical practice. Molecular diagnosticians will need to become comfortable with, and gain confidence in, these new platforms, which are based on radically different technologies compared to the standard DNA sequencers in routine use today. Experience will determine whether these instruments are best applied to sequencing versus resequencing. Perhaps most importantly, along with increasing read lengths inevitably comes increased ascertainment of novel sequence variants of uncertain clinical significance, the postanalytical aspects of which could bog down the entire field. But despite these obstacles, and as a direct result of the promises these sequencing advances present, it will likely not be long before next-generation sequencing begins to make an impact in molecular medicine. In this review, technical issues are discussed, in addition to the practical considerations that will need to be addressed as advances push toward personal genome sequencing.
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