Understanding Results
Understanding Results | ​Positive Result | ​Negative Result | ​
Uncertain Result | ​ Re-analyze Results
Understanding Your Results
It is important to know in advance the types of results you might receive as this may vary from test to test. The genetic changes found on a genetic test result are called DNA ‘variants’. DNA variants may be inherited from a parent or may arise as new changes, called “de novo” variants in egg or sperm cells before conception.
Laboratories classify variants using specific guidelines created by the American College of Medical Genetics and Genomics (ACMG). The classifications include pathogenic, likely pathogenic, variant of uncertain significance, likely benign, or benign:
Benign
Likely Benign
VUS
Likely Pathogenic
Pathogenic
Once the laboratory has completed its analysis, it will typically issue a report that indicates positive, negative, or uncertain results:
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Positive: A genetic change has been found that explains the individual’s symptoms or is associated with a specific condition. The variant(s) identified in a positive result will be classified as pathogenic or likely pathogenic.
GeneDX. Rapid Genome Testing for Neonatal & Pediatric Patients. PDF Resource. https://www.genedx.com/patient-support/
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Negative: No disease-causing or potentially disease-causing changes associated with the individual’s symptoms have been identified in the analyzed genes.
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Variant of Uncertain Significance (VUS): A genetic change has been identified, but there is not enough evidence to determine if the variant is potentially disease-causing or benign. In some cases, testing of parents or other family members may be needed to clarify a VUS finding and may lead to reclassification of the variant.
With genetic testing, there is also the potential to receive unexpected results, especially in the case of exome or genome sequencing. Since exome and genome are typically performed using samples from the individual being tested as well as their biological parents, a family may learn that biological relationships may not be what they had thought.
For example, a family might learn that the biological father is not the individual who submitted the sample, or parents might learn that they are closely related to one another. With exome and genome testing, laboratories also give families the choice to learn about “secondary” findings.
The ACMG has a recommended list of conditions that have onset in adulthood, may lead to significant and serious health issues, and which have guidelines for screening or monitoring. Examples are genes which are related to an increased risk for certain types of cancer or heart disease. It is important to discuss the possibility of unexpected or secondary findings with the provider who is ordering the test.
Amanda Singleton. GeneDx Genetic Diagnostics Powerpoint. Provided by Ilene.
Gene name: Identifies the gene involved in the genetic change. The gene name is typically a series of letters and numbers.
After a Positive Result
After receiving a positive result, the genetic counselor or healthcare provider should first ensure that the result correlates with the individual’s symptoms.
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Understanding the specific variant and gene information may provide a better understanding of the prognosis and associated symptoms which may in turn lead to changes in medication choice, surveillance decisions, diet changes, and care goals.
Smith L, Malinowski J, Ceulemans S, et al. Genetic testing and counseling for the unexplained epilepsies: An evidence-based practice guideline of the National Society of Genetic Counselors. J Genet Couns. Apr 2023;32(2):266-280. doi:10.1002/jgc4.1646
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Positive results may lead to changes in treatment or medical management in 40-60% of individuals across all age groups.
Graifman JL, Lippa NC, Mulhern MS, Bergner AL, Sands TT. Clinical utility of exome sequencing in a pediatric epilepsy cohort. Epilepsia. 2023 Apr;64(4):986-997. doi: 10.1111/epi.17534. Epub 2023 Feb 21. PMID: 36740579.
Individuals may also be referred to specialty clinics or have additional evaluations including consultations with other medical specialists, imaging, or neurodevelopmental therapies. A diagnostic may provide a better understanding of what to expect in terms of future health, growth and development, increased awareness of seizure risk, and may help families to obtain early intervention services such as occupational therapy or speech and language therapy.
A genetic diagnosis may lead to eligibility for clinical trials that are available to individuals with a specific gene variant. These may be accessed through direct referral from healthcare providers or through a online platforms such as clinicaltrials.gov.
Even when there is limited clinical utility for the individual’s current medical management, these results may still be useful to a family by providing recurrence risk information for future pregnancies and allowing for family-member testing
Smith L, Malinowski J, Ceulemans S, et al. Genetic testing and counseling for the unexplained epilepsies: An evidence-based practice guideline of the National Society of Genetic Counselors. J Genet Couns. Apr 2023;32(2):266-280. doi:10.1002/jgc4.1646
Additional personal utility to these results include connection to patient advocacy groups or rare disease communities of individuals with the same genetic diagnosis, connect individuals to other research opportunities as well as provide an answer to an individual’s diagnostic odyssey. Organizations like the Rare Epilepsy Network (REN) contains a community of hundreds of members and partners who can help provide these resources and support. See Section: Why it Matters Now?
After a Negative Result
A negative genetic test result does not mean that a genetic cause of the individual’s symptoms has been ruled out. Instead it indicates that with the current knowledge and technology available the laboratory was not able to identify any disease-causing or potentially disease-causing variants. In some cases, a genetic cause may never be found, and the cause of the individual’s symptoms is not genetic.
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After receiving a negative result, it is important to consider and discuss the limitations of the test with a knowledgeable healthcare provider. Depending on the test ordered, the provider may consider ordering additional genetic tests. For example, if initial testing was a multi-gene panel or chromosome microarray (CMA), further testing might include exome or genome sequencing. In some circumstances additional testing might not always be the best next step. For example, having genome testing immediately after receiving a negative exome result might not significantly increase the likelihood of making a diagnosis. See Section: When to Re-analyze Results
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Smith L, Malinowski J, Ceulemans S, et al. Genetic testing and counseling for the unexplained epilepsies: An evidence-based practice guideline of the National Society of Genetic Counselors. J Genet Couns. Apr 2023;32(2):266-280. doi:10.1002/jgc4.1646
Smith L, Malinowski J, Ceulemans S, et al. Genetic testing and counseling for the unexplained epilepsies: An evidence-based practice guideline of the National Society of Genetic Counselors. J Genet Couns. Apr 2023;32(2):266-280. doi:10.1002/jgc4.1646
Palmer EE, Sachdev R, Macintosh R, Melo US, Mundlos S, Righetti S, Kandula T, Minoche AE, Puttick C, Gayevskiy V, Hesson L, Idrisoglu S, Shoubridge C, Thai MHN, Davis RL, Drew AP, Sampaio H, Andrews PI, Lawson J, Cardamone M, Mowat D, Colley A, Kummerfeld S, Dinger ME, Cowley MJ, Roscioli T, Bye A, Kirk E. Diagnostic Yield of Whole Genome Sequencing After Nondiagnostic Exome Sequencing or Gene Panel in Developmental and Epileptic Encephalopathies. Neurology. 2021 Mar 30;96(13):e1770-e1782. doi: 10.1212/WNL.0000000000011655. Epub 2021 Feb 10. PMID: 33568551.
Beyond additional testing, next steps may also include referrals to research programs or researchers who are investigating undiagnosed conditions, such as the Undiagnosed Disease Network. With continued gene discovery, we are learning more every day about the genetic causes of epilepsy. Given this, re-analysis of exome and genome results is important and may lead to a diagnosis that was not previously identifiable.
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After an Uncertain Result
After receiving a result of uncertain significance (VUS), it is important to remember this is not a diagnosis since there is currently not enough evidence to determine whether the variant is disease-causing or benign. It is also important to note that the interpretation of an individual’s results may vary across different labs. For example, some labs may be more conservative and might report more uncertain variants than others.
GeneDX. Rapid Genome Testing for Neonatal & Pediatric Patients. PDF Resource. https://www.genedx.com/patient-support/
SoRelle JA, Pascual JM, Gotway G, Park JY. Assessment of Interlaboratory Variation in the Interpretation of Genomic Test Results in Patients With Epilepsy. JAMA Netw Open. 2020;3(4):e203812. doi:10.1001/jamanetworkopen.2020.3812
When an individual receives a VUS on their genetic test report, it is important to discuss with their provider whether the variant or gene listed as a VUS correlates with their medical history. To understand the significance and interpretation of a VUS individuals may need to consult with a genetics expert or genetic counselor.
As a next step, the parents of the individual tested may need to provide samples to see if either one of them has the variant. If a parent has the same variant, it could be an indication that the variant is a benign change observed within the family and is not causing the individual’s epilepsy condition. After receiving a VUS, additional genetic testing may be recommended or your provider may refer you to a research programs that specializes in neurogenetics or undiagnosed conditions.
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As new information emerges, laboratories may reclassify variants of uncertain significance to pathogenic or benign, which could change the test result to positive or negative. We recognize one of the challenges with genetic testing can be getting a VUS and finding a change that scientists don’t fully understand yet. This can add a layer of uncertainty, but it is important to remember that genetic research is constantly evolving with new information being discovered every time an individual undergoes testing. Genetic counselors can help you cope with this uncertainty and ensure individuals are getting the most accurate information available.
With genetic testing in epilepsy, there is a suggested tiered approach that has been included in a practice guideline for genetic testing unexplained epilepsies that is endorsed by the National Society of Genetic Counselors.
Smith L, Malinowski J, Ceulemans S, et al. Genetic testing and counseling for the unexplained epilepsies: An evidence-based practice guideline of the National Society of Genetic Counselors. J Genet Couns. Apr 2023;32(2):266-280. doi:10.1002/jgc4.1646
The practice guideline recommends starting with exome or genome testing. Over 1,000 genes have been associated with seizures. This means testing one gene at a time is not effective or efficient. If an individual has already had a single gene test, multi-gene panel, or CMA and the test results were uncertain or negative (non-diagnostic), it is appropriate to pursue broad testing like exome or genome sequencing. Even if the test has high diagnostic yield like exome and genome, there are still limitations to every test and there may be next steps that address these gaps in testing.
Ruggiero SM, Xian J, Helbig I. The current landscape of epilepsy genetics: where are we, and where are we going? Curr Opin Neurol. 2023 Apr 1;36(2):86-94
Smith L, Malinowski J, Ceulemans S, et al. Genetic testing and counseling for the unexplained epilepsies: An evidence-based practice guideline of the National Society of Genetic Counselors. J Genet Couns. Apr 2023;32(2):266-280. doi:10.1002/jgc4.1646
When to Re-analyze Results
Knowledge of epilepsy genetics and testing technology is constantly evolving.
GeneDx reports only about 29% of providers take advantage of reanalysis, despite the fact that 8% of individuals receive a new positive result or a finding in a new epilepsy gene after reanalysis.
Amanda Singleton. GeneDx Genetic Diagnostics Powerpoint. Provided by Ilene.
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ILAE Sharp Waves. Genetic testing in epilepsy: Who, how and why? – Dr. Ilona Krey. 2025.
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If an individual has had exome or genome testing and received an uncertain or negative (non-diagnostic) result, re-analysis is appropriate, particularly 18 months to 2 years after the original test was performed.
To pursue reanalysis:
Contact the provider who ordered the original exome or genome sequencing test and ask them to reach out to the genetic testing lab that performed the test to request reanalysis. When doing so, you should encourage the provider to share any new clinical updates such as new symptoms they are experiencing or any family members with similar symptoms.
Amanda Singleton. GeneDx Genetic Diagnostics Powerpoint. Provided by Ilene.
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If reanalysis of the sequencing data is not possible and the individual received a VUS from their original test:
Ask your provider to check with the lab to see if the variant has changed classification (variant reanalysis) . Similarly, you should encourage the provider to share any new clinical updates such as new symptoms you are experiencing or any other family members with similar symptoms.
Amanda Singleton. GeneDx Genetic Diagnostics Powerpoint. Provided by Ilene.
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Amanda Singleton. GeneDx Genetic Diagnostics Powerpoint. Provided by Ilene.
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If you cannot reach the original healthcare provider who ordered your test, you can contact the lab that completed the testing, and ask them to initiate reanalysis. The lab may be able to connect you with a genetic counselor to help you understand the reanalysis results.
Amanda Singleton. GeneDx Genetic Diagnostics Powerpoint. Provided by Ilene.
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