Remember the Human Genome Project?  It cost about $3 billion and took 13 years (1990 to 2003) – and that was with 20 labs around the world working in parallel.  A commercial lab can now sequence your whole genome in a few days for about $600.  Now the problem is how to recognize a “abnormal” result and what to do with that information.  We all have mutations that our parents don’t, and most of those have no health implications.  The problem is knowing which ones do.  This makes it medically and ethically tricky to interpret the results of a whole-genome sequence. 

Until that knowledge base improves, whole-genome sequencing will probably be useful mainly in assaying for known mutations in well-studied genes.  It is also possible to roughly predict the health implications of a never-before-seen mutation in a well-studied gene by working out the amino acid substitution that would result in the protein being encoded.  Then, using the physical and chemical principles of protein structure and function, one could roughly predict how that amino acid substitution might affect the function of the protein.  But that’s still an inexact science.  Besides, a lot of the genome doesn’t encode proteins at all – it has regulatory functions, which sometimes involves encoding small stretches of RNA that in turn regulate protein production.

So, with those challenges in mind, here’s a bit of speculation as to what might be in store, near-term, for genetic testing in the routine clinical care of PSP.  Thanks go to my friend and colleague Alex Pantelyat, MD of Johns Hopkins for his input.

• Once effective treatments for PSP arrive, we may find that people with different variants in the gene encoding tau (or other gene) respond differently to specific medications.  This might be especially true for treatments targeting the process where the information in the DNA is encoded into proteins (called “transcription”).  Right now, short stretches of DNA or RNA called “antisense oligonucleotides” (ASOs) that interfere with the encoding of the normal form of tau are in clinical trials.  As you’d imagine, this risks side effects caused by a lack of normal tau protein.  But if we knew what gene mutation was causing PSP in an individual, an ASO could be specifically tailored for it. 
• It will become standard practice for clinical trials of any sort of treatment to be designed for people with, or without, specific gene variants.  Or if a trial doesn’t try to restrict enrollment in that way, it will at least do the sequencing at the time of enrollment and apply the genetic information retrospectively to check if the treatment works in people with specific gene variants. 
• As discussed in my last post, variants in the LRRK2 gene help determine the duration of survival of people with PSP, though they don’t affect the risk of developing the disease to begin with. There are bound to be other genes with similar effects.  Sequence data from such genes could be useful to people with PSP and their families in preparing for the future financially and emotionally.
• The last point, about prognostic genetic markers, is about single-gene variants.  But the same point could apply to combinations of variants in multiple genes where no single variant has a measurable effect. 
• Using a battery of gene variants as a high-accuracy diagnostic test for PSP (as opposed to prognosticating a rate of progression or what symptoms might develop next) seems unlikely to come to pass, as the list of genes already linked to PSP probably are the most informative ones, and they are insufficient as a diagnostic test.  But if that list is coupled with other non-genetic tests such as MRI, PET and blood tests for tau or neurofilament light chain, a highly accurate test battery could result. 

Beyond the $600 lab fee are the bills for the necessary interpretation and counseling, which add about $2,000.  While the lab fee has been declining because of technological improvements, the other services are provided by human beings and are only likely to rise.  Insurance companies, Medicare and Medicaid don’t presently cover any of this unless it’s for someone with cancer or a very ill newborn.  I assume this is because we don’t yet have enough use for the data in terms of alterations in management.  But what are the financial implications if my above predictions come true and actionable uses do become available?  PSP is a rare disease, but what if similar uses of whole-genome sequencing are developed for Alzheimer’s, atherosclerosis, depression and the many other diseases where genetic variants, or combinations thereof, affect disease risk or prognosis?   Even if we manage to reform the medical payment in the US and improve access to that system for those presently under-served, who will provide all that counseling? And who will respond to patients’ demands for preventive treatment? And who will pay for that treatment? Scary.