There are many variations from individual to individual, and most of these differences simply represent genetic diversity within a population. People have different hair colors, eye colors, and heights, but if someone is born missing both arms, then the difference is of greater significance. The same philosophy holds true for genomes; most of the variants in a DNA sequence are meaningless, but geneticists work to identify the few variants that are responsible for diseases. Ingenuity Variant Analysis is one tool that makes this job a little easier. Using various filters and one’s knowledge about the disease, a geneticist can limit the number of variants from hundreds of thousands to just a few. This list of genes and variants will then undergo further analysis.
During our internship in the Family Genomics group of the Hood Lab, we used Ingenuity in the context of case studies. We were presented with patients who experienced a range of symptoms, from mitral valve prolapse to pheochromocytoma to psychomotor delay. Many of them had previously been diagnosed with a certain disease, but our role was either to support these diagnoses or make a new one based on genetic evidence.
First, we would be given a list of symptoms that the patient experienced and a family background for related phenotypes. After creating a pedigree for the patient, we would use databases such as OMIM to identify possible causes for these symptoms. By researching various diseases, we would create a list of candidate genes to further investigate. Finally, we would use Ingenuity to further limit our list and hopefully identify the root cause.
For example, for this particular case, the 33 year old man was diagnosed with Marfan Syndrome, which correlates to the gene FBN1. He experienced symptoms such as aortic dissection and scoliosis, so we researched other explanations. Among these, we found one condition called Loeys-Dietz Syndrome, which is associated with the gene TGFBR2.
We applied five different filters.
Confidence ensured that we were only looking at accurately sequenced variants. There may often be technological, so confidence screens out variants that were of low quality.
Common Variants limited the list of variants to ones that were less prevalent in the population. Since we were handling a rare disease, we only want to look at rare variants, rather than meaningless ones that most people have in their genomes.
Predicted Deleterious kept variants that were known to have adverse effects on the patient. Since we are identifying a harmful disease, we want to look at variants that interrupt important signaling pathways or gene expression.
Genetic Analysis limited variants to ones that were consistent with the predicted inheritance pattern. By examining the pedigree, we could determine that the disease was likely to be dominantly inherited. Therefore, we kept variants that were heterozygous in the genome.
Biological Context kept variants that were consistent with the experienced symptoms. We entered phenotypes such as scoliosis and aortic dissection.
After this analysis, the one remaining variant was in the gene TGFBR2, which was present on our candidate gene list and consistent with the patient’s symptoms. Therefore, we could confidently conclude that the patient had Loeys-Dietz Syndrome rather than Marfan Syndrome.
Ingenuity is a powerful tool that allows us to process genetic variants in an efficient and effective manner. It was an incredible experience learning how it works, and how geneticists approach these sorts of problems.
Ingenuity: Variant Analysis - http://www.ingenuity.com/products/variant-analysis