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TruGenome Undiagnosed Disease and TruGenome Undiagnosed Disease Trio Tests Intended Use Statement The TruGenome Undiagnosed Disease and TruGenome Undiagnosed Disease Trio Tests are intended to provide information to physicians to aid in the diagnosis of inherited diseases of single‐gene etiology (Mendelian diseases). The analysis and interpretation are designed to detect and report on single nucleotide variants and small insertion/deletion events found within genes that have established association to genetic disease [as found in the national Genetic Testing Registry (www.ncbi.nlm.nih.gov/gtr) and Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/omim)]. The analysis considers autosomal recessive, autosomal dominant, de novo or X‐linked inheritance, as well as clinical presentation, family history, and peer‐reviewed literature. These tests are most appropriate for situations where the evaluation of multiple genetic markers may clarify or refine the diagnosis because the presenting set of symptoms and tests are inconclusive, there are a large number of candidate genes to evaluate, or the phenotype might indicate multiple genetic conditions. This test is intended to be used by physicians with established genetics expertise. Genetic counseling and consenting should be done by a qualified medical geneticist or genetic counselor that is familiar with the performance characteristics and intended use of these tests. Examples of conditions or suspected conditions for which these tests are appropriate include mitochondrial conditions, inherited cardiomyopathies, conditions involving multiple symptoms such as seizures, organ involvement, and dysmorphology, degenerative neurogenetic conditions, etc. The tests are appropriate to evaluate inherited cancer predisposition syndromes, such as Lynch syndrome or hereditary breast and ovarian cancer, but are not intended to identify somatic cancer variants for the purpose of guiding therapy. For some conditions, such as muscular dystrophy, the tests might be an appropriate reflex or follow‐up to help resolve inconclusive results (e.g., clinical presentation consistent with disease, but most common type(s) of mutations not detected using standard‐of‐care testing). Examples of conditions for which these tests are not appropriate include those that are caused by multiple genes or gene‐environment interactions, such as type II diabetes, non‐syndromic isolated developmental delay/autism spectrum disorders, and autoimmune disease. Methods, Performance Characteristics, and Test Limitations Whole‐genome sequencing is performed via next generation sequencing (NGS) using DNA extracted from whole blood. The regions of the genome not reported here include regions where the human reference genome has not been completely resolved, or where duplications of genetic regions make it impossible to align the fragments accurately. Examples of genes that are associated with regions of high gene duplication events and therefore are not technically appropriate for analysis include, but are not limited to, immunoglobulin, HLA, the SMN genes for Spinal Muscular Atrophy, and telomeres. Contact the laboratory for specifics regarding ability to make calls in the regions of specific interest. The data are aligned and reported according to build 37.1 of the Human Reference Genome (www.ncbi.nlm.nih.gov/projects/genome/assembly/grc/human/). We sequence to an average of GEN‐032‐00 Current as of 20 October 2013 ≥ 30‐fold coverage. Our validations demonstrate that 30‐fold coverage with quality scores of ≥ Q30 results in calls having greater than 99.99% accuracy in detecting SNVs in a diploid genome. The minimum call depth is 10‐fold, which corresponds to > 98% sensitivity in detecting SNVs. Less than 3% of our total reported data are at 10‐fold coverage. Deletion events in the range of 1–11 base pairs and insertions in the range of 1–3 base pairs are reported with a specificity of > 99.95% and sensitivity of > 80%. The tests are able to detect inherited variants, but not somatic variants or heteroplasmy. TruGenome Clinical Sequencing Services are performed in the Illumina CLIA (Clinical Laboratory Improvements Amendment)‐certified and CAP (College of American Pathologists)‐accredited Clinical Services Laboratory. The TruGenome Sequence information is generated by licensed personnel using an analytically validated process. Consistent with Laboratory Developed Tests, it has not been cleared or approved by the U.S. Food and Drug Administration. This genome sequence information can be analyzed to potentially aid your physician in the evaluation of a broad range of health conditions or physiological traits. You will not receive medical results, or a diagnosis, or a recommendation for treatment from Illumina. Any results arising from the analysis of your genome sequence information that might be deemed medically actionable should be confirmed using alternative testing. If you have any questions or concerns about what you learn through your genome sequence information, you should contact your physician or a genetic counselor. Currently Illumina does not accept orders for TruGenome Clinical Sequencing Services from New York. GEN‐034‐00 Current as of 20 October 2013