15q11.2 – the microdeletion spectre

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.

21 thoughts on “15q11.2 – the microdeletion spectre

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  10. Interesting! Alas, still no answers.
    After seeking medical genetics for answers due to my strong family history of developmental delays with some dysmorphisms before deciding on having children or not; my middle son whom I’ve felt “has it” was found to have microdeletion 15q11.2 with any more family testing pending at this point. I had long said “I hope he is not having some sort of seizure and we’re all missing it!” due to his behavior besides his other behavioral disturbances. I had, indeed, asked for an EEG before but it had not been done. After this diagnosis it was done and found to be abnormal with focal spiokes in and we’ve just seen the peds neuro “epileptologist” without any certain answers.

    • Dear Tina,
      thank you for sharing your story. Counseling in 15q11.2 microdeletion carriers is very difficult given that this variant is a risk factor that can be associated with a wide range of neurodevelopmental presentations, but is also present in individuals without disease. As I mentioned in my post, the 15q11.2 variant cannot give “certainty” or “answers”. In fact, most clinical decisions (how to interpret EEG findings etc.) would probably be done independent of the genetic finding by most physicians.
      As a brief disclaimer, I would like to add that the “Channelopathist” is a research blog. As I am sure you can understand, we don’t give medical or genetic advice and recommend bringing any relevant questions with your treating physician.

      Ingo

      • Hi Ingo,
        I am wondering if you are familiar with chromosome 21q deletion? Having less then 1MB deletion (actually 722 kb) on chromosome 21q and never had any health issues.
        I was told it’s huge deletion but I see that microdeletion is called up to 5 MB.
        If it’s not inherited is it possible I can pass that to my child?
        Please answer to me with any information you know about this specific deletion.
        I am an individual with normal health and normal (beautiful) physical appearance, without any mental issues.

        Thank you so much!

        N.

      • Dear Nia,
        thank you for your message. I would like to start by pointing out that we are research blog and that do not give advice with respect to medical or genetic questions. We know that there are always many questions about genetic findings and suggest that you discuss this particular issue with you health care provider or geneticist.
        Having made this disclaimer, let me try to discuss some of these issues in general terms. On chromosome 21q there are several regions that are associated with genetic syndromes or are found in patients with genetic diseases. The role of many of these variants is not clear and some of them may also be found in unaffected, that is healthy individuals. Assessing the risk for disease in a child is difficult as your geneticist/genetic counsellor would need to sit down with you and look at where this deletion is located and what is known about this in particular (chromosome 21q is quite large…). Some of these deletions are also found in many healthy individuals and are not thought to increase the risk for disease.
        I am sorry that I cannot provide a more satisfying answer, but as you can tell from my answer, this is a complicated matter due to many aspects.

        Best wishes,
        Ingo

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  15. Dear Ingo,

    thank you very much for your reply. The way I understand is that I am healthy but I might be a carrier for my future child. The genetic counselor told me exactly where is deletion and how much but she also said that there are no cases similar to mine. Which means they can’t tell if I will develop some disease in the future. I was sent to cardiologist but they found nothing unusual, my heart is healthy.
    I was offered for my future pregnancy to consider ivf but also there are 75% chances to have a healthy pregnancy.
    All I know it’s very rare and there are no cases to compare with.
    No family history about any genetic disorder.
    Both of my parents are in their 60’s and still in good health.

    Thank you,

    Nia

    • Dear Nia,
      again, my reply should not be meant as a medical or genetic advice, but simply as a scientific statement on a research blog. It is actually quite common that people are the only “carriers” of a certain genetic variant. And in most cases, we don’t know more about this other than that a given healthy person carries it. This may already be true for small deletions and duplications, but this is even more true on the level of the base pair sequence. Such “rare variants” are a huge problem when it comes to telling causative from “benign” genetic variation.

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