Genetic mirage. We look at genetic variants all the time. There are few genetic variants that stare back at us. 15q11.2 is one these variants, facing us with the constant question how we define and perceive genetic risk. Not because of its pathogenicity, but because of the confusion that it causes.

I have seen the enemy – and he is us. Please take a minute, google “15q11.2” and look at the results. You will find an empty web page at the Office of Rare Disease Research and OrphaNet, a lonely reference on the website of an Angelman Syndrome self-help group and some posts from confused parents on message boards. What does it mean if you’re 17 weeks pregnant with a fetus carrying a 15q11.2 deletion? In fact, 15q11.2 is one of the more frequent search terms that lead people to our blog. This was my motivation to write this post and to talk about genetic risk and how we perceive it. In fact, 15q11.2 is as much about the person dealing with the deletion as it is about the deletion itself, it is about the enemy within ourselves. I first came across the famous 1971 Pogo Earth day poster during my Logic 101 class at the University of Kentucky. Our professor asked us to code this phrase in logical statements. This turned out to be quite difficult, given that this phrase is reflexive. It relates back to the speaker.

Pogo, porkypine and 15q11.2. I have seen the enemy and he is us. Source: Wikipedia. We too believe that using this low resolution reproduction qualifies as fair use under United States copyright law.

A brief primer on the genetics of 15q11.2. This microdeletion is one of the genetic disorders that occurs due to the duplication architecture of the human genome. The genomic regions on the left and on the right of this microdeletion are almost identical (segmental duplications), which may results in a misalignment when DNA is replicated. When the replication machinery skips the part between both segmental duplications and the genomic region between is deleted, a microdeletion has occurred. Microdeletions are causes of many genetic disorders including Angelman Syndrome or DiGeorge Syndrome. Also, some microdeletions have a wide range of associated disorders such as the 15q13.3 microdeletion. These are the diseases that we compare 15q11.2 to when we think of genomic disorders. And this results in a psychological phenomenon called anchoring heuristic.

How bad is 15q11.2? Anchoring refers to the fact that our perception of a given situation is influenced by using comparisons. If microdeletions at 15q11-q13 (Angelman) or 15q24 result in severe disease, how can 15q11.2 be any different? In addition, early publications have found this microdeletion in patients with neurodevelopmental phenotypes including intellectual disability with speech delay. Subsequently, 15q11.2 was found to be a recurrent genetic variant associated with schizophrenia and behavioral disturbances. Not a variant to take lightly, the literature suggested at the time. However, the picture slowly changed. Studies in epilepsy and intellectual disability helped to delineate the risk carried by this variant, and a 2010 study by Vassos and colleagues tried to estimate the penetrance of this microdeletion. 15q11.2 has an odds ratio of 5 and a penetrance of 3-7%. Taking the odds ratio as a proxy for an increase in risk, 15q11.2 carriers are fives times more likely to develop disease than non-carriers and have a risk of 3-7% to develop disease at all. This is not the usual picture you see in severe genetic diseases. 15q11.2 does something, but it is not a black and white thing. More than 95% of individuals carrying the 15q11.2 microdeletion are unaffected.

Some more biases. Up to 0.5% of all individuals in a population are 15q11.2 carriers. According to this, it is quite likely that one of our colleagues or one of the EuroEPINOMICS researchers is a 15q11.2 carrier- and you have just caught me introducing another bias. If we think about our friends and colleagues carrying this variant, we introduce another anchor. If they have this variant, it can’t be too bad. But where is the truth? What should we tell patients and families and should we tell them at all?

Non-directiveness and informed decision making. Risk in and of itself is meaningless, but statistics like an odds ratio are always context-dependent. If we try to explain the risk of 15q11.2, we need to be aware of what the context is. One principle of genetic counseling in this context is non-directiveness. Never use the phrase “I personally would do xyz”. This usually makes a genetic counselor cringe as we are patronizing the other person by adding our personal views into the equation. Dealing with risks like this may best be approached by providing a broad range of understandable information and offering different perspectives to the enemy inside.

Ingo Helbig

Child Neurology Fellow and epilepsy genetics researcher at the Children’s Hospital of Philadelphia (CHOP), USA and Department of Neuropediatrics, Kiel, Germany