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.
You’ve received and understood a genetic report with a variant in SYNGAP1. You’ve checked if the variant is pathogenic, and if not you’ve read about Variant of Unknown Significance (VUS). Maybe you even found the variant on Clinvar. But you still have many questions:
You may worry that your loved one’s SYNGAP1 variant might be rare, and will not be a target for cures. This is not true. Nothing could be farther from the truth.
Below are some thoughts that may help you in thinking about your loved one’s genetic report, from JR (SRF Volunteer and Genetics PhD) and the SRF leadership team.
Some genetic diseases run in families, and the variants are inherited through the generations. Many diseases that work this way are recessive, where a person with one pathogenic variant is a carrier, and a person with two copies of the pathogenic variant has the disease (homozygous). Sickle Cell Disease is an example. This is NOT how SYNGAP1 works, which is modified by phrases like autosomal dominant, heterozygous, de novo, haploinsufficiency, and occasionally germline mosaic or somatic mosaic.
SYNGAP1 is a dominant disease, characterized by only one of the two copies of the gene having a pathogenic variant (heterozygous), and is created by a new change (de novo), meaning that the pathogenic variants arise anew. Another way to describe this is that unaffected (non-SYNGAP) parents do not have the pathogenic variant, just the child has the pathogenic variant, just the child has the symptoms and the medical disorder. The disease cause is haploinsufficiency, meaning one is insufficient: one working copy of the gene is not enough. In order to have typical functioning, both copies of the SYNGAP1 gene must work.
Mice that are homozygous for SYNGAP1 mutations do not survive past a few days after birth. No humans have been recorded with pathogenic variants in both copies of SYNGAP1. It is thought that homozygous pathogenic variants in SYNGAP1 would be unsurvivable.
De novo variants are present in all of us. “Every time human DNA is passed from one generation to the next it accumulates 100–200 new mutations, according to a DNA-sequencing analysis of the Y chromosome.” This is part of the natural variation that occurs in our human species. The vast majority of these changes are benign, harmless, never noticed in people. The SYNGAP1 gene is in a small percentage of the genome that can cause a big problem when one of our two copies is altered. The major isoform contains 1,343 amino acids, which is a large target. For comparison, the average protein has about 300 amino acids. In a sense, every one of the pathogenic variants in SYNGAP1 is rare, even the handful of variants that are currently known to be shared by a few patients.
Clinical geneticists use different types of genetic tests to look for different types of genetic variants. Some types of variants can be seen by karyotype analysis (visual assessment of banding in a chromosome squash); some are seen by tests for Copy Number Variants (CNV); some are seen by single gene sequencing, by exome sequencing (all coding regions), or by whole genome sequencing. Knowing which tests were done, and which were also performed on biological relatives if they are available, is important when assessing whether a variant causes symptoms in a patient.
SYNGAP1 is one of over 20,000 genes in the genome. Variants in other genes may have major or minor influence on the clinical symptoms of disease. Some people with a SYNGAP1 VUS may have one or more pathogenic variants in the genome not yet identified. Some patients may have a set of VUS in multiple genes.
There are a few categories of variants:
1. The variants that are benign do not harm the person. One frequent example is a single nucleotide change that codes for the same amino acid (called a synonymous change).
2. The variants that have unknown significance are called Variants of Unknown Significance (VUS). The molecular genetics and the clinical data are not strong enough to form an opinion either way.
There are several types of variants that are pathogenic (or likely pathogenic):
3. A single nucleotide change in the protein coding sequence that introduces a premature stop (called nonsense). This is one of the ways to make a Protein Truncating Variant (PTV). This results in a shortened version of the protein being expressed that is thought to be immediately discarded by a process called Nonsense-mediated Decay (NMD), so it is thought that the altered protein is not present to perform any functions. Nonsense variants are well understood. These are considered haploinsufficiencies (one working copy of the gene is not enough). Nonsense comprises ~33% of variants in Ciitizen to date.
4. A small deletion or insertion in the protein coding region that shifts the reading frame, resulting in a messed up code and always stops early, is called a frameshift. These are also well understood. This is another of the ways to make a PTV, and the shortened proteins are thought to be immediately recycled by NMD, so it is thought that the altered protein is not present to perform any functions. These are also considered haploinsufficiencies. Frameshift comprises ~38% of variants in Ciitizen to date.
5. A single nucleotide change in the protein coding sequence that turns one amino acid into another is called a missense, and it can alter a function of the protein. These are not well understood, and more research is needed to understand each one. Missense variants could be haploinsufficiencies, or could have a partial loss of function, or they could have a new function, (although no gain-of-function variants have yet been discovered for SYNGAP1). Clinical evidence of symptoms is very important for every category but has especially high importance in this category. Missense comprises ~13% of variants in Ciitizen to date.
6. A small insertion or deletion that adds or subtracts one or up to a few amino acids. Some positions in the coding region might tolerate a change like this, but many positions could not. Like missense, these are not well understood, and more research is needed to understand each one. Clinical evidence of symptoms is very important for every category but especially high importance in this category. We see fewer of these than missense, they comprise <5% of variants in Ciitizen to date.
7. A change in an intronic region. Introns are spacers of DNA between the protein coding regions (exons), and are edited out in the RNA (through a mechanism called splicing). Changes here might be tolerated, or might alter splicing or regulation of expression. Aberrant splicing can lead to insertions or deletions of amino acids, or can introduce a frameshift (see above). RNAseq (currently not a standard clinical test) will help describe each intronic variant. Clinical evidence of symptoms is very important for intronic variants. Intronic variants make up ~9% of the variants in Ciitizen to date.
8. A large insertion or deletion that affects the entire gene. If the entire gene is gone, perhaps other genes are gone too. If the entire gene is duplicated, perhaps other genes are too. Each one must be looked at as an individual and look at the endpoints of the alteration and try to figure out the entire change, not just the change to SYNGAP1. We see few of these, they comprise <5% of variants in Ciitizen to date.
Any size alteration can occur, not just the ones listed here. Some are complex and include multiple changes all at once.
Most strategies being developed should be useful for all the variants in a category, as shown in Table 1 here. Even the strategies that work one at a time for specific alleles (for example, base editing and prime editing) are being developed with the goal of being able to fix variants across the entire gene. How does any treatment strategy develop? One step is looking at the technology in patient-derived cell lines.
The iPSC lines being started by SRF represent a much bigger set of patient-derived variants than most researchers would ever hope for. We have looked at the variants from every angle -- from the point of view of the DNA, the RNA, the protein -- in an effort to understand the range of variants amenable to each treatment strategy. The goal is to have iPSC lines made from every category of pathogenic variants so that scientists can easily test their treatment strategies. The more helpful and involved a patient community, the better chance we have for engaging researchers from both academia and corporations.
Everyone has some tiny chance of being born with SYNGAP1. The question asked by families is how likely is it that a subsequent sibling of a Syngapian will also be a Syngapian? The answer requires an understanding of mosaicism.
Germline mosaic: If parents have no symptoms of the disorder but have more than one biological child with the exact same variant, that is evidence that the de novo mutation occurred in either the paternal or maternal germline (testis or ovary). This is called germline mosaicism, where a fraction of the cells in the germline are typical and the complementary fraction of cells are heterozygous for the new SYNGAP1 variant. The likelihood of subsequent pregnancies being affected by the same SYNGAP1 variant increases but is not known exactly. The highest it could be is 50%, if all the cells of the germline are affected. The lowest is the same rate in the general population for any birth. At this point germline mosaicism is assumed after multiple births with the same de novo variant.
I am sorry I do not have a reference for this next set of statements, but it describes the understanding I came to in 2002 after long conversations with our geneticist and genetic counselor, and it helped me frame my decision whether to have another child. For humans in general, boys are born with 97% having no issue at birth (3% risk of “something wrong at birth” for boys) and girls at 98% having no issue at birth (2% risk for girls). As a general rule, for any family that has a biological child with a genetic disorder, the risk of any issue at birth increases by two-fold for additional pregnancies. “Any issue at birth,” meaning a new disorder or the same disorder again or even something that is not a genetic disorder like a difficult birth. This means that in the absence of other information, a pregnancy following one with a SYNGAP1 diagnosis has 94% chance of being a typical boy (6% risk) and 96% chance being a typical girl (4% risk), doubled risk for each sex. Why is the risk less for female humans? The primary reason is because males have one X chromosome and females have two. So for critical genes on the X chromosome, there is a “backup” for females but not for males.
Somatic mosaic: if the affected SYNGAP1 patient has the variant but shows a weak signal in the sequencing test, it is evidence for somatic mosaicism. That is where some of the cells in the person are typical, and some of the cells harbor the heterozygous SYNGAP1 variant. Often a second tissue will be tested to find the rate of mosaicism in another tissue (checking the blood vs. cheek swab for instance). The clinical symptoms of a SYNGAP1 pathogenic variant with somatic mosaicism is often less severe, as only some cells have a deficit. If the affected individual is considering having children, there is a chance that they pass on a SYNGAP1 variant to their children, depending on where the affected cells are in the body.
The occurrence of both types of mosaicism show the “earliest” and “latest'' developmental time frame that a de novo variant arises. Developmental time in this case refers to the state of the tissue when the DNA variant arises (germline, zygote, early embryo) and follows cell divisions after the variant occurs. Most often new mutations arise at or around the zygote (one-cell stage of the new baby), and there is no mosaicism in the parental germline and no mosaicism in the patient. The earliest the de novo variant could arise is as a mosaic in a parent that includes germline mosaicism. The latest it can arise is in the embryonic stage of the patient when a few cells go on to form the embryo. See more on SYNGAP1 mosaicism.
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