Syngap parents, please stop worrying about Schizophrenia!

SCIENCE

FEBRUARY 11, 2019

Your child has been diagnosed with a Syngap1 mutation, and you are now diving into understanding everything you can about it. With Intellectual Disability, Epilepsy, and Autism Spectrum Disorder at the forefront of your mind, you feel overwhelmed already. When scientific articles pop up with the words “Syngap” and “Schizophrenia” in the title, what’s a parent to think? We are here as a couple of parents of Syngap kids who also happen to be basic research scientists, to give you our take on how schizophrenia is involved with the Syngap gene.

First, we state that our Syngapians share a genetic feature: specifically, a new (de novo) mutation in one copy of the Syngap1 gene that leads to a reduction in the level of Syngap protein to half of what it should be. Decreasing the protein by half causes our Syngapians’ symptoms; any genetic disease that is caused by a reduction of half the protein is called haploinsufficiency. Bottomline: To-date, there is ZERO clinical data to suggest that haploinsufficiency of the Syngap1 protein will result in schizophrenia.

Second, we tackle three papers you may have seen individually, and end with final thoughts.

1. Comprehensive functional annotation of susceptibility SNPs prioritized 10 genes for schizophrenia (PDF)

Recently, there was a blind posting of an article about schizophrenia that lists Syngap1 as a “target gene” without any explanation of the methods, results, or implications for our Syngap population.

Reading about any association of Syngap with another condition may cause anxiety, and it may be especially high given the stigma of schizophrenia. The above paper did not study our Syngap population: as stated above, our Syngapians have a de novo mutation within the Syngap gene. Instead, this study looked in groups of people with and without a schizophrenia diagnosis to find markers that have been passed down through populations: markers that are linked to a schizophrenia diagnosis. Bottom line: If there are schizophrenia diagnoses in your family tree, you may be interested in this study. If not, this article is not for you.

Our Syngapians have a new (de novo) mutation (that their parents do not have). In rare cases, the de novo mutation happened in mom’s ovaries or dad’s testes. But in all cases, mom and dad do not have the new Syngap mutation in their own brain tissue. de novo mutations cannot be studied at the population level, because they are new, not currently present in the population. Bottomline: Reading association studies will not help you understand your Syngapian. De novo mutations do not show up in association studies. Fine print: if you have genome wide SNP (single nucleotide polymorphism) data for your Syngapian, your genetic counselor or geneticist might have information for you from association studies.

2. Syngap1: Mind the Gap (PDF)

This article has a quote that might alarm some. “Although several studies have shown the role of Syngap1 mutations in neurodevelopmental disorders, little is known about its relevance to schizophrenia… (Hamdan et al., 2009) did not find any de novo mutations, splicing or truncating, in their patients with schizophrenia.” Bottomline: The types of mutations that gave our Syngapians their diagnoses are exactly the types of mutations they did not find.

3. The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity. (PDF)

Let’s talk about the basic research going on with Syngap. Where in our bodies is the protein? It is expressed in a subset of neurons, in a subset of synapses, on the receiving end at the membrane where the signal is captured and relayed (called the post-synaptic density). The post-synaptic density is the largest protein machine in the human body, and while scientists know a lot about it, the amount they don’t know about it is greater. What is the Syngap protein structure? The Syngap protein has many different forms, with optional starting and ending sequences. The bulk of the protein contains domains that interact with other proteins (PH, C2) and a domain that signals (Ras-GAP). It likely has other features that are yet to be identified. When and where are the different end sequences used? And why? What proteins does Syngap directly touch, and what happens to those proteins when the amount of Syngap protein is reduced? These are questions that basic research scientists are trying to answer right now. In fact, they started wondering before any of us had a Syngapian.

After years of work, in 2003 Richard Huganir’s lab published a mouse knock-out of Syngap, where they deleted a portion of the gene. It is not clear whether this particular mutation models the mutations in our kids. Huganir’s lab and others are currently developing mouse models that exactly mimic mutations in our kids, and we look forward to hearing those results. Bottomline: If you see a “Syngap model” mouse or rat or fish, it may or may not reflect the type of mutations found in our kids. It takes a hard read to figure things out, and by that we mean that scanning journal titles does not equal education.

So I read everything and understand I shouldn’t worry but why are scary things associated with Syngap? Isn’t Syngap enough? Yes. Syngap with Intellectual Disability, Epilepsy, often Autism, and sleep issues, is enough. The confusion comes from the following: We are calling our kids Syngapians. But that is shorthand for “de novo Autosomal Dominant haploinsufficiency of Syngap1” or “new heterozygous mutation resulting in truncation of Syngap1” or many other ways you could say the same thing. But Syngap is a gene, a region of the chromosomes (Syngap-associated SNPs), and a protein. It isn’t just the name of our disease: it is the name of all of that, and that protein can be altered in different ways that may in fact be involved in autism spectrum disorders (without ID and epilepsy), bipolar disorder, schizophrenia, and potentially other things too. So if you have a google alert for Syngap papers, you’ll be getting lots of interesting things to look at. Just don’t make the mistake of thinking that they all have to do with your Syngapian. Most of them won’t.

The good news: The more Syngap research that happens, the more researchers that are interested, the more funded researchers studying other things who find a way to insert Syngap research into their projects, the better off our field of research will be. So while we work in the trenches, and hope for treatments, we may be seeing journal article titles that needlessly scare us. You already know your kids. You already love them.