What We Get From Genetic Testing

Hint: It's not everything you paid for You've all seen the ads for direct to consumer (DTC) testing. Several companies are out there. They'll take your sample and send you the results of the genotyping assays they've worked out. It may be a large number of variations (like 600 thousand) or a small focused panel of about 40 to 60 variations. You send them the money and the sample, and they send you the data. Simple, right? Yes and no. It is a simple transaction and there is data there. But data isn't the answer to your question. Data is what their machine spits out. The answer to your question is information, and that's a little harder to come by.  Each genetic testing company has a report they send you or give you access to on the web. It may be on their whole panel or it may be on a subset. Hopefully, the report will tell you if you have the non-variant form (wild type) and what the variation means if you have it. You'll want to know how common it is, what happens to people with it, and what it means for your health. And a lot of companies' reports tell you those things. So far, so good.  But genetics are actually far more complicated than the products we've been sold so far. There are gene-gene interactions and gene-environment interactions that aren't taken into consideration. There's the context in which the variation occurs; that is, how other variations change the action of that variation. So you get a test and it tells you that you are at higher risk for an illness when you aren't. You may change your lifestyle or even something more drastic in response. Alternately you may get a result that tells you you are at lower risk when you aren't. In short, we need more than we're getting.  The future is now All the things I've said above apply to genotyping, the targeted measuring of changes at individual known locations. That's one technique of genetic testing. But there's a whole other world out there, and it's a lot bigger than genotyping. We've been limited to genotyping by cost, but the costs for this other type of technique are going down rapidly. So get ready for the future: sequencing.  With sequencing, we don't just read one spot to see if it is different. We read an entire stretch to see what's different. It's much more of a discovery process than genotyping, because we may actually find variation where no one has seen variation before in the genome. Instead of measuring one base pair in a gene with 17,000 base pairs, we're looking at them all.  It's a lot more data. And it could be a lot more information. One day, it will be. But today, not so much. People have gotten so used to genotyping, that the sequencing industry has found a way to take a lot of the potential information out of any reporting. Sequencing reports About 5 years ago the American College of Medical Genetics and Genomics(ACMG) and the Association for Molecular Pathology (AMP) published a paper in which they set up standards for genetic lab reporting of data. Among the points the paper makes is that only members of the authoring societies should be able to tell people what their data means. Now who would have predicted that?  They also set up a complicated algorithm to evaluate each variant to one of 5 categories: Benign, Likely benign, Uncertain, Likely pathogenic, and Pathogenic. If that looks familiar, it is. It is the five point Likert scale so popular in psychology and polling: Agree very much, agree, don't agree or disagree, disagree, disagree very much. The Likert scale is popular because it makes sense to the primate brain. I either care or I don't. I either care a little or a lot. Five points to simplify any situation. In essence, the ACMG criteria is mapping primate psychology onto molecular biology. A lot is lost in the translation.  But remember back to genotyping where we were looking only at one change and one disease and not paying any attention to interactions? Well, we still aren't here. ACMG is still focused on what are referred to as Mendelian illnesses. That is, one gene, one disease. Gene-gene interactions don't fit well into the five categories. Nor do risk factors for other things, or variations that don't do anything by themselves unless a certain environmental stimulus comes by. So a lot of the benefit of sequencing gets sequenced out by ACMG based reporting. At the end we have a list of variants that look a lot like a genotyping report. Well, sequencing is a lot more expensive, so shouldn't we get more? Yes, and we can. The future is tomorrow Every sequencing machine produces a number of files for every sample. In the end, though, it spits out a file type called Variant Call Format (VCF). It's a listing of the hundreds of variants from wild type that the sample has for the regions measured. That sound great, right? All the variations and what they all mean to me. That's what I want. Well, not so fast. By convention, all the variations that are Benign or Likely benign are filtered out. And the ACMG criteria take out most of the rest. An example is a variant in the gene APOE that is involved in cholesterol levels. The variant is known and has an rsid if you want to look it up (rs7412). It occurs in about 8% of people, and ACMG uses a 5% cut off for Mendelian disease. So if something occurs in more than 5% of people, it can't be pathogenic. If you were to get a sequencing test of APOE from a lab that uses ACMG, you'd probably never find out if you had a variation at rs7412. Even though OMIM considers it pathogenic, Clinvar lists it as pathogenic, and PharmGKB considers that it is a very important variant for the use of certain cholesterol lowering meds, your doctor and you will probably never know you have the variation.  But that's the present and I told you we'd be talking about the future. Wouldn't it be nice if the labs, like the DTC testing companies do, gave you not only their report, but the raw data as well. If you're paying $1000 for a test (or your insurance company is), shouldn't you get all the data that was created by the test? And if the lab can't give you all the information about that data, wouldn't you like someone else to have a site where you could upload your data and get the answers you need?  So you're probably wondering, "Can I send my VCF file to GenEd for that information?" The answer today is, no, but not because we can't do it. We could. But almost no one has their VCF file. The sequencing companies keep them. We don't want to put the resources into building a tool that no one can use.  But maybe we're wrong and you have your VCF file. Well, if you want this tool, let us know. Maybe the demand is there. And in the mean time, if you want us to look at your VCF file, drop us a line. We're happy to help.