Mosaicism and what it means to be a “carrier” of SYNGAP1

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This article is written by SYNGAP1 parents for SYNGAP1 parents. It is not medical advice. Our intention with this article is to enable families to have informative conversations with geneticists, genetic counselors, and other medical professionals.

When it comes to SYNGAP1 disorder, mosaicism essentially means that some cells in the body have a pathogenic (disease causing) SYNGAP1 genetic mutation and the rest are normal and fully functional. This article discusses loss-of-function mutations that result in haploinsufficiency, causing intellectual disability, often with autism and epilepsy. Previously, this was called MRD5. When we say “the mutation” we mean a heterozygous dominant loss-of-function mutation in SYNGAP1. Examples include mutations that cause a stop within the protein coding region, a splice mutation, and some amino acid changes.

To discuss mosaicism we will describe three different classes that are seen. The different classes are based on when the mutation occurred: early or late in the developing embryo, or in a parent’s body.

1) Most de novo mutations are not mosaic

For most SYNGAP1 patients, the mutation happened very early on, either in their parents egg or sperm cells, or very soon after the egg and sperm joined together to create the zygote. In this case all (or the vast majority) of the cells in the SYNGAP1 patient carry the mutation.

2) Two types of mosaicism: with and without SYNGAP1 symptoms

For mosaic SYNGAP1 patients, the mutation happened some time later in the development of the embryo, which means some of their cells continued to split and develop without the mutation, and some split and developed with the mutation, leading to a patchwork of cells with or without the mutation in different spots in the body.

Have you ever seen a mosaic tile or pavement? That is a simple visual of how the cells end up in a mosaic person.

Texture library © 2019 Dmitriy Chugai
Texture library © 2019 Dmitriy Chugai

If the mutation happened early enough during the initial cell divisions, the mutated cells end up riddled throughout the body in patches, including the brain, causing some degree of SYNGAP1 disorder. This is called somatic mosaicism. Somatic means cells of the body. There are a few known low-level somatic mosaic patients, both within the online communities and in the literature[1]. These patients are thought to have a somewhat milder form of SYNGAP1 disorder because some of their cells are normal (more on that later).

Sometimes, if the mutation happened later on in the development of the embryo, the patches of mutated cells are limited to a smaller region or tissue. Sometimes a patch will be limited to the ovary or testis. This is called germline or gonadal mosaicism and is a subset of somatic mosaicism. A person with germline SYNGAP1 mosaicism would likely not show any symptoms of SYNGAP1 disorder because the cells in their brain are not affected.

Most SYNGAP1 disorders are de novo (new, spontaneous) and therefore not inherited from either the mother or father. The exception to this are people with either low-level somatic mosaicism or germ-line mosaicism. They, like affected SYNGAP1 patients, are carriers of the SYNGAP1 mutation and have a 50% chance of passing it down to their children. If a patient’s mother or father is a carrier of SYNGAP1, then all that patient’s cells will have the mutation because the mutation is present from the very start of conception. Likewise, SYNGAP1 mosaicism is always de novo and it is not possible for a mosaic parent to have a mosaic child. Therefore, if parents already have one biological child with SYNGAP1, unless the child is mosaic, it is worth getting tested to find out if either of the parents have low-level mosaicism. It is also informative to have any future embryos tested for SYNGAP1.

How can you find out if you have mosaicism and are a carrier of SYNGAP1?

Somatic mosaicism can be detected from testing cells of the body (a simple blood draw or cheek swab will work). Germline mosaicism however, can only be detected by testing the egg or sperm cells. This is difficult for two reasons: 1) obtaining egg cells is not straightforward and, 2) the egg or sperms you choose to test may not have the mutation, leading to a possible false negative result.

So what should a parent of a SYNGAP1 child do if they want to have more biological babies? First, rule out low-level somatic mosaicism with a blood test or cheek swab. Secondly, for each future pregnancy, utilize non-invasive screening panels which can detect SYNGAP1 mutations through a blood test [2]. Taking a sample of the placenta through amniocentesis can also indicate the presence of SYNGAP1 mutations in the fetus. Finally, if getting pregnant through IVF, perform pre-implantation genetic diagnosis on the embryos to rule out SYNGAP1 disorder.

What is the prognosis like for somatic mosaic SYNGAP1 patients?

We don’t know for sure. It depends both on how many mutated cells exist and their location, neither of which we can truly measure without doing an autopsy of the brain. A blood test can only determine the extent of mosaicism in the blood cells. Some genetics labs will release a percentage of mutated cells found in the blood, others will not. The reason why some labs won’t is that blood cells are not the best approximation for the brain cells. So even if you are told you’ve say a 20% somatic mutation in the blood, it could be higher or lower in the brain where the SynGAP protein is expressed. A blood test is also a point in time sample. So the percentage reported could change when another sample is tested. Skin cells are a better approximation for brain cells because they originate from the same cell line during fetal development (ectoderm). Families may opt to do a skin biopsy to get a better approximation, but ultimately we don’t know what percentage of SYNGAP1 mutated cells will result in symptoms. The overall percentage may not even matter if the cells are concentrated in one particular area of the brain or another. Lastly, SYNGAP1 is a spectrum disorder, with severity of symptoms not yet linked to any particular mutations. So it is very difficult to say the severity or symptoms for a mosaic person.

Explanatory graphic from Poduri et al [6]
Explanatory graphic from Poduri et al [6]

Of the somatic mosaic SYNGAP1 children known to the family community, they have many of the same symptoms, delays and challenges as other SYNGAP1 kids and typically require the same therapies. However, they are known to walk and talk. There are also germline mosaic parents known to the community who are themselves unaffected. In the literature we know of one mosaic father who had a more severely affected daughter. He is described as having learning difficulties[1]. We don’t yet know of any very low-level somatic mosaic patients who are completely unaffected or very mildly affected.

Mosaicism in other diseases

A recent study of mosaicism of various epileptic encephalopathies found that 8% of apparently unaffected parents had some form of low-level or germline mosaicism. Most parents were symptomless or had minor symptoms (e.g. febrile seizures as a child)[3].

A study of mosaicism of Dravet patients also found that patients with mosaicism had on average a milder presentation of the disease[4].

In other genetic disorders, such as Down syndrome, mosaic people are also thought to be sometimes more mildly affected, however the percentage of cells detected in the blood has not been found to be an accurate predictor of outcome. [5]

Footnotes

  1. Berryer et al, 2013, Mutations in SYNGAP1 Cause Intellectual Disability, Autism and a Specific Form of Epilepsy by Inducing Haploinsufficiency.
  2. Vistara Non-Invasive Prenatal Test https://www.natera.com/vistara
  3. Meyers et al, 2018, Parental Mosaicism in “De Novo” Epileptic Encephalopathies
  4. De Lange et al, 2018, Mosaicism of de novo pathogenic variants in epilepsy is a frequent phenomenon that correlates with variable phenotypes
  5. Mosaic Down Syndrome https://www.chop.edu/conditions-diseases/mosaic-down-syndrome
  6. Poduri et al, 2016, Tracking the Fate of Cells in Health and Disease