Background

The Genome Sequencing test aims to end the diagnostic odyssey for individuals with rare genetic disorders, ultimately guiding clinical care for patients and their families. This test provides physicians with high quality genome sequencing, as well as unparalleled data interpretation. Results will be returned to the ordering physician in a concise report featuring an overall test result and in-depth phenotype-driven interpretation of known or plausible genetic causes of disease. Patients have the option to expand the report to include clinically actionable secondary findings (unrelated to the primary indication for testing) in 59 genes.

Genome Sequencing Consultation

If you would like assistance in determining the appropriateness of genome sequencing for your patient, you may contact us by phone or submit pages 2–3 of our requisition form, along with your contact information, and we will contact you.

Indication for Testing

Testing is currently recommended for individuals with a suspected genetic disorder in whom traditional genetic testing has not yielded a result, despite a suspected genetic etiology. Genome sequencing may also be considered as a first-line testing strategy for conditions with a high degree of genetic heterogeneity for which panel-based testing is either limited or unavailable.

Methodology

Genome sequence is generated from genomic DNA that is fragmented and barcoded followed by sequencing on the Illumina HiSeq X instrument with a minimum coverage of at least 20X for 95%. Technical sensitivity of this assay is 99.84% (95% CI: 99.83-99.85%) and positive predictive value is 99.18% (95% CI: 99.12-99.24%). Reads are aligned to the NCBI reference sequence (GRCh37), using the Burrows-Wheeler Aligner (BWA), and variant calls are made using the Genomic Analysis Tool Kit (GATK). All disease-associated variants on this report are confirmed via Sanger sequencing or another orthogonal technology.

Methodology for PGx if included: Genotype calls for specific genomic positions are identified using the Genomic Analysis Tool Kit (GATK) and a custom script. Diplotype, phenotype, and dosing information are generated using the Clinical Pharmacogenetics Implementation Consortium (CPIC®) and PharmGKB guidelines. The following pharmacogenomic variants are detected by this assay: TPMT: rs1800462, rs1800460, rs1142345, rs1800584; CYP2C9: rs1799853, rs1057910, rs28371686, rs9332131, rs7900194, rs28371685; VKORC1: rs9923231; CYP4F2: rs2108622; IFNL3: rs12979860; DPYD: rs3918290, rs55886062, rs67376798, rs72549309, rs115232898, rs1801266, rs78060119, rs56038477, rs72549303, rs1801268,rs75017182; SLCO1B1: rs4149056; CYP2C19: rs4244285, rs4986893, rs28399504, rs56337013, rs72552267, rs72558186, rs41291556, rs12248560; NUDT15: rs116855232; CYP3A5: rs776746, rs10264272, rs41303343. Additionally, variants in G6PD, RYR1, and CACNA1S associated with pharmacogenomic recommendations are reported, if identified.

Limitations

Specific types of genetic variation, such as triplet repeat expansions, structural variation, and copy number events are currently not reliably detected by genome sequencing. Additionally, while genome sequencing covers ~95% of the genome; there are certain regions for which the assay may fail to adequately generate sequence information. Moreover, not all disease-associated genes have been identified and the clinical significance of variation in many genes is not well understood. Variant interpretation may change over time if more information becomes available. Gene-level coverage information for both tests is available online and details regarding the coverage of genes associated with a specific indication can be determined upon request.

For additional questions, you also may visit our Frequently Asked Questions page.