Toward a Solution for Unexplained Epilepsies: NSGC’s New Consensus Recommendations
As a genetic counselor, some of the hardest cases are the ones with the most straightforward indications. Seizures, for example, are extremely common, occurring in 1 in 10 people over their lifetime. Epilepsy, or recurring seizures, impacts 1 in 26 people. In genetics, we’re used to dealing with the rare. Like a detective, we’re used to looking for clues in a patient’s health and family histories to figure out what is causing the problems we see, so we can help determine what problems may come next. With common maladies, like seizures, there are so many possible causes.
From the viewpoint of the genetic counselor in clinic seeing a patient with unexplained seizures, you worry about missing the little detail that might help figure out what’s going on. A detail that might give a family a diagnosis and more information about the future. But in the great majority of cases, there is no clue. It’s “just seizures.” Seizures, to a parent, might be the scariest thing imaginable, stirring up many emotions and thoughts of the unknown. Many people with seizures do well, and seizures can be controlled with treatment or may go away with age. However, for others, seizures may get worse. Seizures are also associated with autism spectrum disorders and intellectual disability. For the genetic counselor, it used to be that if there were no additional clues, there was no chance to give the family an answer. However, with today’s technology combined with the latest guidance, we now stand a much stronger chance.
If we take a step back in time to when the genetics healthcare provider didn’t have next-generation sequencing as a tool, we find that there weren’t really any means to search for the genetic cause of a patient’s epilepsy. Gene discovery had begun by the turn of the millennium, but clinical testing was rare, targeting only families with multiple affected individuals. Plus, testing only would have impacted a very small proportion of children with epilepsy even if it were widely available. With Sanger sequencing, testing for the average patient would have been time consuming and expensive, and positive results would have been rare.
As next-generation sequencing became commonplace, gene discovery accelerated. Now, hundreds of genes are known to be associated with epilepsy. And next-generation sequencing allows us to test many of them at the same time. The majority of unexplained epilepsy is now assumed to have an underlying genetic etiology. However, with the rush of new technology, different clinicians are using different testing strategies for these patients. Without the evidence to support a consistent strategy, providers are led to practice inconsistently within and between clinics, leading to healthcare inequities.
With such rapid progress, what is the best way to test? And what is the optimal way to counsel these patients? Previous guidelines may have noted the value of genetic testing, but an optimal strategy had not been proven. All that changed recently when, in combination with data from a systematic evidence review, NSGC released evidence-based consensus recommendations for approaching genetic testing in epilepsies. Two recommendations were made:
1.) Genetic testing should be offered to all individuals with unexplained epilepsy, without limitation of age, with exome sequencing/genome sequencing or a multi-gene panel (>25 genes) as first-tier testing followed by chromosomal microarray if testing was normal.
2.) Genetic testing should be selected, ordered, and interpreted by a qualified healthcare provider in the setting of appropriate pre-test and post-test genetic counseling.
Now, in the case where a patient has “just seizures,” we have the resources and evidence to suggest a path forward for all families. We have the hope of finding answers for so many more families than we could help before. And as technology advances, the yield for genetic testing may exceed fifty percent. That’s a huge amount of progress in a couple of decades.
Genetic diagnosis for epilepsy may have direct implications, such as choice of medication, initiation of specialized diet (ketogenic), or qualifying an individual for clinical trials. It may also provide information about a poor prognosis, which may lead to reduction in additional invasive tests or procedures, or the decision to pursue palliative care. A diagnosis also informs about health risks for other family members and for reproductive planning for patients and families. By having a guideline for all providers to follow, we remove one of the barriers to healthcare equity for those with epilepsy and allow more patients to receive the benefits that come with diagnosis.
— Jamie Zdrodowski, MS, CGC
