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Covering the Bases: Implementing Genome Sequencing into Clinical Care

Mimi Padmabandu
| Aug 16, 2013

Genome at your fingertipsIn 2009, Illumina established a CLIA-certified, CAP-accredited Clinical Services Laboratory to offer whole human genome sequencing services to physicians and genetic counselors. Last week, the Clinical Services Laboratory provided a brief glimpse into their environment, the process of clinical whole-genome sequencing, and the impact that genome sequencing could have on healthcare.

The Classic “Whodunnit?”

When looking for variation in the genome, the Clinical Services Lab focuses on single nucleotide variations (SNVs) at this time, which can be missense, nonsense, or silent mutations. The identified variants, each potential “suspects,” are then evaluated while trying to answer the question: “Could this variant be responsible for or involved in disease?” As in any investigation, the first step involves gathering evidence. The lab collects a variety of information about the disease, gene, and variant2, through literature reviews3 and annotated databases.

Each identified variant is then classified into one of 6 categories. Pathogenic variants denote those in which there is sufficient information linking the variant with disease and the lab has a high level of confidence quality of the information available. . The category likely pathogenic is used for variants where there is sufficient information to indicate that the variant is likely involved in disease, but there is less confidence in the quality of the information.  Differentiating between pathogenic and likely pathogenic classifications helps indicate to physicians where further due diligence may be needed before taking action.  Variants declared unknown significance – suspicious are those that have been reported in a single or very limited number of cases and are weakly suggestive of pathogenicity.  There is not enough information about the relationship between this variant and disease for the variant to be classified as likely pathogenic, although the information available is suggestive of a relationship with disease. Variants of unknown significance have incomplete, contradictory, or no information available. The remaining variants fall into one of two categories: likely benign or benign. Likely benign variants are functionally normal and have been reported in one or no cases  with little or no control data, or may be present in a high percentage of the population making it too common to reasonably be associated with disease. A variant is classified as benign if it has been reported  in more than one case with control data establishing the lack of association with disease, is well established in the literature as a benign variant, and is functionally normal

With these criteria in mind, the lab’s Individual Genome Sequencing (IGS) Test includes whole-genome sequencing from blood or extracted DNA at a depth of 30×. After identifying and classifying SNVs, the Clinical Services Lab delivers a clinical report, a technical report, a clinical appendix, a genome VCF (gVCF) file, array-based genotyping calls, and a MyGenome app key to the physician.

From Data to Doctor

Sequencing technology has already proven itself to be of tremendous value in the clinical setting. The Pulitzer prize-winning series One in a Billion chronicles the story of Nicholas Volker, a young boy with a rare, severe form of inflammatory bowel disease. By the time he was four years old, Nic had undergone more than 100 operations, and had exceeded his health insurance lifetime cap by age 5—still without a diagnosis. Using exome sequencing, researchers examined 16,124 variants and narrowed them down to one causative variant in the XIAP gene. This variant is so rare that it has not been reported in anyone but Nic and his mother. From rare disease identification to rapid diagnosis of genetic disease in newborns, sequencing technology is continuing to gain momentum in the clinical environment.

However, finding a variant doesn’t always mean a treatment, or even a diagnosis. A good case for clinical whole-genome sequencing has a strong suggestion of a genetic cause, which entails thorough genetic evaluation and family history information. After sequencing, an identified variant must then be thoroughly supported as likely pathogenic or pathogenic in the literature for it to be considered clinically actionable. Genetic counseling is a very important step in deciding whether to pursue clinical testing.

Clinical Sequencing for Healthy Adults

Clinical sequencing isn’t only useful for diagnosing rare disease. Research has uncovered significant findings from mostly healthy adults, including Factor V Leiden, hereditary breast and ovarian cancer, hereditary hemochromatosis, hereditary hearing loss, and many variants that indicate carrier status for a variety of disorders.

The Understand Your Genome (UYG) conference presents a unique, hands-on opportunity to explore the possibilities of genomic healthcare. During this two-day event, the Illumina Clinical Services Lab sequences each participant’s genome, interprets variants found in any of approximately 1600 genes involved in about 1200 diseases, and provides each individual with his or her genome sequence on an iPad to view using the MyGenome app. Currently containing over 30,000 variants, the laboratory’s database is continuously expanding with every genome analyzed. The advent of long-read technology holds even more promise, as this innovation may enable clinical sequencing to analyze larger structural variations. To learn more about a patient’s perspective on personal genome sequencing, read Carole Cadwalldr’s article What Happened When I Had My Genome Sequenced, describing her UYG experience and how sequencing is revolutionizing medicine.


1 1000 Genomes, Ensembl, NHLBI Exome Sequencing Project

2 Human Gene Mutation Database (HGMD), Leiden Open Variation Database (LOVD), ARUP mutation database, Gene Reviews, Online Mendelian Inheritance in Man (OMIM), Single Nucleotide Polymorphism database (dbSNP), ClinVar, SNPedia

3 PubMed, Google Scholar