Genetic testing advice

I’ll plagiarize myself again. CurePSP asked me to write up a piece in response to someone asking if a person with PSP or CBD (or suspected PSP or CBD) should have genetic testing. The short answer is mostly “no,” but here are the details:

People with an established diagnosis of PSP or CBD and a close relative with one of those conditions (or a strong suspicion thereof) should consider having their MAPT gene sequenced.  That’s the gene encoding the tau protein.  But the vast majority of those with PSP or CBD have no similarly affected relatives, and for them, genetic testing is neither necessary nor useful.

The test should sequence the entire MAPT gene and not merely check for the ten mutations, all of them very rare, that have been associated with PSP (seven with CBD) in the past.  If the person with the disorder (called the “proband”) proves to have a mutation in MAPT, then other family members with similar symptoms can be tested as well. 

Variants in eight genes other than MAPT have been associated with PSP and five with CBD, but each of these raises the disease risk only slightly and testing for them is not useful in an individual or even in a family.  That’s because these are only “marker associations,” not specific mutations altering a protein known to be involved in the PSP process. The markers are called “single-nucleotide polymorphisms” or “snips” and unlike the MAPT mutations, they incriminate a span of about 100 or so genes, not a specific gene, much less a specific mutation that can be tested for.

We must keep in mind that many mutations, even in genes like MAPT, are harmless and do not cause disease.  Sixty MAPT mutations have been reported in humans so far, and only ten of them are known to cause PSP. So having a mutation in MAPT and having PSP doesn’t necessarily mean that one caused the other.  If a relative with the same symptoms has the same mutation, it may still not be cause-and-effect, but if that relative is distant, or the proband and two or more relatives share symptoms and a mutation, then the likelihood of cause-and-effect is greater. 

Even if there’s a good statistical likelihood that the proband’s mutation is the cause of their disease, and a healthy relative proves to have the same mutation, one still would not be able to predict how soon the relative might start to develop symptoms.  That information could be available soon from some other type of “pre-symptomatic” or “predictive” testing, but no such test has yet proven to be sufficiently accurate in such a situation.

People with suspected PSP or CBD with no relatives with similar symptoms have no need for genetic testing.  Even if one of the known PSP/CBD-causing mutations were found, it would not contribute much to the likelihood of PSP or CBD as the diagnosis explaining the symptoms.  The same is true for the healthy relatives of someone with established PSP/CBD.

So, as you can tell, estimating disease risk from genetic testing can be complicated.  That’s why a professional genetics counselor or a physician with expertise in adult neurogenetics should advise anyone considering having family genetic testing for PSP or CBD. Don’t just rely on the simple report supplied by 23andMe.

I’ll update this as necessary.

2 thoughts on “Genetic testing advice

  1. Dr. Golbe,

    For familial PSP (or PSP mimics) where there is a mutation, do you believe the age at which symptoms appear is determined entirely on genetics? Or do you think outside factors, such as environmental triggers, etc still play a role in disease onset?

    • Hi, Joey:

      Thanks for asking that. Many single-gene diseases with strong familial occurrence have widely varying onset ages in the same family. So far, the only things that have been found to affect onset age in PSP are genetic, but those mutations don’t come close to explaining all of the onset-age variance, and in any case, those studies were done in non-familial PSP. There are undoubtedly more genes to be found that affect onset age in both familial and non-familial PSP, but the effect of environmental factors has barely been explored. So the answer to your excellent questions is that we don’t know yet.

      Also, don’t forget that the most important factor could be neither genetic nor environmental, but “stochastic,” which is just a fancy word for “random.” In this case the randomly occurring event would be the misfolding of a single tau molecule. It sticks in that abnormal shape and then templates that shape onto nearby normal tau molecules, producing a chain reaction of tau misfolding and aggregation that spreads through the brain. The timing of the initial misfolding and the speed with which the process templates and spreads probably depends heavily on the exact shape and location of the abnormal fold in the tau molecule, which could be under genetic, environmental or stochastic control. Yes, it’s complicated.

      Dr. Golbe

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