JR is a SynGAP parent with a PhD in Genetics, she is an active member of the SRF parent Medical-Science team.
A genetic report describes locations in the patient’s DNA that are different from what is expected. Most of the differences, called variants, are classified as benign (not harmful in effect) or likely benign, pathogenic (causing disease) or likely pathogenic. If you are one of the minority of families faced with a Variant of Unknown Significance, or VUS, it is hard to know what to think or feel. A VUS is truly that -- research scientists, medical doctors, and specialists like geneticists and genetic counselors simply do not have enough information about the gene to know or predict the effects of the genetic variant reported. Keep reading to learn more about how to think about a VUS and what steps a family might take to learn more.
VUS findings in a genetic report occur in many settings, including cancer risk, diseases arising from changes in multiple genes, and single gene disorders. This discussion is aimed only at pediatric neurodevelopmental disorders, where the parents do not display the same features as the patient, and a variant is in only one copy of the two genes we inherit from our two parents.
SYNGAP1-related Non-Syndromic Intellectual Disability (NSID) is a neurodevelopmental disorder, with symptoms starting in early childhood. People with a pathogenic variant in the SYNGAP1 gene may have to deal with learning difficulties, epilepsy, Autistic features, sensory processing differences, sleep disturbances, low muscle tone, communication and eating difficulties, and more. People who are affected in this way by a variant in the SYNGAP1 gene are fondly called Syngapians by their families. The “typical” Syngapian doesn’t exist, as our kids can have vastly different levels of seizures and communication, to name just two highly prevalent issues. There is a typical genetic report, however.
A typical genetic report describes the variant in the SYNGAP1 gene as de novo (new). Pathogenic SYNGAP1 variants usually originate at conception, and are not typically found in the patient’s biological parents. A typical genetic report has a finding that one copy of the gene (heterozygous) is broken. SYNGAP1-related Intellectual Disability is considered a haploinsufficiency, meaning that having only one working copy of the gene causes a lowered level of SYNGAP1 function, and the symptoms of the disorder. And a typical genetic report includes a pathogenic (causing disease) or likely pathogenic finding.
Pathogenic and likely pathogenic variants include those that stop the protein before it is complete (protein truncating variants, some splice variants, insertions and deletions), those that delete a copy of the gene (copy number variants and large deletions), and those that partially reduce the amount of functional protein (some splice variants). In these cases, enough is known about how genes operate to be confident in assigning a pathogenic or likely pathogenic classification. If you want a deeper explanation of how to read a genetic report see this article.
Other types of changes in the DNA sequence have hard-to-gauge effects on gene function. For example, a change in one amino acid might reduce the amount of functional protein, or it might not. Even a change in the gene that does not change an amino acid might have an effect, or it might not. No matter the variant type or its location in the gene, if it is designated a VUS, it means that professionals are not currently sure of the consequence of the variant.
The status of a VUS can change to either benign or pathogenic with new information. Your genetic counselor has most likely already talked to you about looking at the DNA of the biological parents to search for the same variant. If a parent (without SYNGAP1-related NSID) has the identical variant, the variant is considered benign in the patient.
Another place to look for new information is in the ever-growing genetic databases of variation in healthy populations. When a variant is in a database describing natural variation, it can be classified as benign.
If a research lab can study the effects of the variant in question in an animal model system, the human VUS would be predicted to have similar effects. Please note that this is not a current test available, but is the type of basic research needed in order to better understand the range of genetic variants that cause SYNGAP1-related NSID.
Geneticists and testing companies are getting better at predicting the effects of DNA changes on gene function. Data sets are constantly growing, and Artificial Intelligence tools are improving. As time goes on, we will be better able to predict the effects of VUS findings.
Many geneticists, including Dr. Heather Mefford of St. Jude’s Children’s Research Hospital in Memphis, TN and Dr. Gemma Carvill at the Fineberg School of Medicine at Northwestern University in Chicago, IL, are searching for additional genetic changes that impact diseases like epilepsy and neurodevelopmental disorders. They are searching in the entire genome, including areas that don’t code for proteins, and their findings will help genetic reports be more conclusive.
A biomarker is something measurable that correlates with disease, where the severity of disease is reflected in the level of the biomarker. Biomarkers can come in the form of testing bodily fluids (such as blood, saliva, spinal fluid, urine), imaging like MRIs or X-Rays, or measuring movements like brain waves with an EEG or eye movements, or recording behaviors, and more. Currently there are no biomarkers that correlate with SYNGAP1-related NSID, but they are highly sought after. Once biomarkers are identified and clinical tests are available, they will be another source of information to describe a patient’s symptoms. Understanding clinical symptoms is an important part of classifying variants.
If you have a genetic report with a VUS, every year or two you may want to go back to your geneticist to see if any new information has changed the status of the VUS. Here are three questions you might bring to your genetic counselor or geneticist at follow-up appointments.
What can you do today? Sign up with SRF to get updates on the latest research on biomarkers, genetic variant status, and to get support. Whatever combination of genetic reports and clinical features got you to consider a SYNGAP1-related NSID diagnosis, it is worth support and information.
Over time, Variants of Unknown Significance will be sorted into benign and pathogenic categories. Until then, join any communities you might be part of through a VUS and learn more about what may be ahead, including potential treatments. Welcome! We are all learning as we go.
Invitae Corporation (a genetic testing company) has an extensive explanation of variant classes, and builds on the current (ACMG, see below) standards. Invitae.com/en/variant-classification
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. 2015. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424. pubmed.ncbi.nlm.nih.gov/25741868