Genetic Testing – What You Should Know

The Importance of Genetic Testing

Parents notice delays in their child’s development and behaviors before anyone else. Their little one may not be crawling, babbling, sitting up, or walking as quickly as their peers. Although parents are often assured that their child will catch up, that’s not always the case. Therapies may be initiated to address these delays, but in many cases, parents still feel worried, isolated, and dismissed. Genetic testing may uncover the answers needed to provide a clear roadmap for support, connect with a dedicated community, and empower your child’s healthcare providers to identify the best care options. Finding the root cause of your child’s symptoms may open a new world of treatments, testing, and possibilities for targeted therapies that have been proven to benefit children with similar conditions.

Those of us in the SYNGAP1 community found each other because of a diagnosis based on genetic testing that was indicated by symptoms; however, we know that there are many more patients out there undiagnosed. These patients are missing the knowledge gained from appropriate and current genetic testing. The latest quarterly SYNGAP1 Census counts the number of diagnosed patients that have been in touch with CURE SYNGAP1 or our global partners. Because anyone living with SYNGAP1-Related Disorders (SRD) without a diagnosis or without having contacted a SYNGAP1 patient advocacy group is excluded from this count, and there are new patients found every quarter, we recognize that the census is a significant under-representation of how many people in the world actually have SRD. We empathize with families who are still searching for answers to unresolved concerns. But we have learned that although a diagnosis is devastating, it is the necessary foundation upon which we begin building a supportive future for our children.

CURE SYNGAP1 hopes that through this page and its resources, we can help those without a diagnosis on their own journey toward treatments and a possible cure. We encourage you to share this page with families affected by autism or epilepsy, as well as anyone seeking answers behind complex medical symptoms. Regardless of what a genetic test uncovers, it’s highly probable that at least some of parents’ questions are answered, and tools may be available to help their child.

Types of Genetic Testing: A Quick Guide

The path to a diagnosis usually involves one of three primary types of genetic tests. The difference between them is “how much” of your child’s DNA the test can read.

1. Symptom-based Panel (Epilepsy Panel, ID Panel, Autism-associated Panel)

This is a targeted test that focuses only on a specific list of genes associated with one or more broad classes of symptoms.

How It Works: The lab captures and reads only pre-selected genes. Crucially, modern epilepsy panels include the SYNGAP1 gene.
When It’s Used: It is often the first genetic test a child receives after their first seizure, as it is relatively fast and has a high chance of finding a known genetic cause.

2. Whole Exome Sequencing (WES) via NextGen Seq (massively parallel, short read)

WES is a more complete look at the genome than a panel. WES reads the instructions (called exons) for all ~20,000 genes in the body, covering approximately 2% of the entire set of DNA, called a genome. Most known genetic diseases are found in the coding regions.

How it Works: It scans all of the important instructions in the child’s body to look for errors that a focused epilepsy panel would miss.
The Technical Reality: While WES is comprehensive, different testing companies look at slightly different areas of the genome. Some “hidden” parts (like the connectors between genes, called splice sites and introns) can be difficult for WES to read reliably, meaning it may sometimes miss a very rare or complex mutation.
Plus or CNV: in addition to whole exome sequencing, which is great at finding small and single nucleotide changes, a type of test called Copy Number Variant analysis looks for larger stretches of missing (or duplicated) DNA. WES plus CNV is more comprehensive than WES alone.
Trio: Since the vast majority of SYNGAP1-causing variants are typos, and not found in the parents’ DNA, findings in the patient are often checked in the biological parents.
If No Conclusive Diagnosis: Don’t despair if your WES test is inconclusive. After asking for Trio and CNV, one can ask for updates every year or two to see if more is known about how to categorize any Variants of Uncertain Significance (sometimes called Variants of Unknown Significance or VUS).
If these tests do not lead to a diagnosis, but symptoms overlap with Neurodevelopmental Disorders and/or Developmental and Epileptic Encephalopathy, ask for option #3….

3. Whole Genome Sequencing (WGS)

WGS is the most powerful and complete test available. It reads the entire genome—every single piece of DNA in the child’s body.

How it Works: It reads all 6 billion pieces of your child’s genetic code, including all the instructions and the non-coding regions that WES does not report.
When it’s Used: WGS is often used if previous testing was negative but a child still has strong SYNGAP1 symptoms. Adding CNV and Trio analysis (with biological parents) is suggested when available just like with WES.
Cutting Edge Tests (sometimes used in research rather than clinical care): Nanopore Sequencing is a newer type of test that can find even more types of mutations than WES plus CNV Trio or WGS plus CNV Trio. RNA-Seq from patient-derived cells can determine the changes caused by variants that change splicing of the RNA (variants found at the boundary of the exon/intron or within the intron, near the exon).

Which Test Did Your Child Have?

Knowing which test was used to find your child’s mutation helps you understand their specific SYNGAP1 variant and can guide future discussions with your genetics team.

How Do I Get Genetic Testing?

Ask your child’s doctor for assistance. You may find that doctors have varying affinity for ordering genetic testing. Options if you face resistance:
1. Ask other specialists.
2. Find a new doctor aligned with your desire for cutting edge information.
3. Ask the clinician to note in the chart that testing was requested and denied.
Request genetic testing from your neurologist or any children’s hospital; if warranted, they can reach out to a geneticist to have the test performed, as well as provide you with names of genetic counselors for help with interpreting the results.
If the genetic report is anything other than pathogenic, consider asking for a reanalysis of the data every 2 years, as the reference genome is evolving as more individuals have sequence information.
Keep asking questions—do not give up! Affordable testing can be located.

Notable Resources for Whole Genome Sequencing

Program Type

Target Audience

Sequencing Type

Cost

Broad Institute Rare Genomes Project	Undiagnosed rare disease, US resident	WGS	Free to eligible
Rare Genomics Institute (RGI) Next Generation Sequencing	Undiagnosed rare disease	WGS (facilitated)	Free to eligible
BeginNGS (Rady Children’s)	Newborns at participating hospitals	Rapid WGS	Free to eligible
GUARDIAN Study (New York)	Newborns at participating NewYork-Presbyterian hospitals	WGS (~400+ conditions)	Free to eligible (opt-in)
Sunshine Genetics Pilot (Florida)	Newborns born anywhere in Florida, state-wide access	WGS (~750+ conditions)	Free to eligible (opt-in)