Personal stories from parents who have struggled to find the cause of their children’s epilepsy have a consistency to them: there are moments of disbelief, anger and frustration, great difficulties, and, quite often, a commitment to persevere. While it is often hard for an outsider to imagine these families’ lives, it is clear that epilepsy can be a frightening disorder for both those suffering from it and their families. Fortunately, our ability to diagnose, treat, and advocate for individuals with epilepsy improves with each passing year.
Epilepsy is a common neurological disorder resulting from chaotic electrical activity in the brain. An estimated 65 million people are affected worldwide, and the disorder has a prevalence of 4 to 8 per 1,000 individuals.1,2 At least half of all epilepsy cases are thought to have a genetic etiology,3 and we have seen tremendous progress in the last decade in uncovering the plethora of genetic causes and biological pathways affected in epilepsy.4 With that complexity comes a daunting problem: because epilepsy shows extreme genetic and clinical heterogeneity, it can be difficult to establish a specific diagnosis for a patient in the clinic and to select a gene to test to confirm that diagnosis.5 As a result, it’s important to cover all your bases when considering genetic testing for epilepsy.
The advent of next-generation sequencing (NGS) now makes it possible to test many genes at once and at relatively low cost. Covering your “bases” in this case is literal: using an NGS gene panel ensures good sequence coverage of all nucleotides in the tested genes, a critical element in completing molecular testing for a suspected diagnosis. A negative result from a genetic test should not leave one wondering if a normally detectable pathogenic cause was missed. (Exome sequencing can be a useful test after a negative result on a targeted panel, although it is considerably more expensive and may lack sufficient sequence coverage to be used as the first test.) Invitae’s epilepsy test sequences at deep coverage up to 103 genes for a variety of epilepsy conditions. It was designed to capture the major causes and also includes a range of newly characterized epilepsy genes. Aside from investigating changes in the DNA sequence itself, Invitae’s test also simultaneously and reliably detects loss or gain of DNA in these genes, which is critical in testing many epilepsy-causing genes.
Why is it important to utilize genetic testing in epilepsy? Covering all bases also means not missing a critical diagnosis that could potentially guide treatment. In some instances, identifying the genetic cause for epilepsy can inform clinical management by pointing to treatments that can dramatically curtail or eliminate the seizures, ameliorate concomitant clinical features such as intellectual disability,6 or even identify contraindications (situations in which a drug could be harmful). Invitae’s epilepsy panel includes a number of genes associated with treatment implications, including SLC2A1, SLC6A8, ALDH7A1, PNPO, POLG, TSC1/2, and SCN1A.
What other bases should be covered? Genetic testing is proving increasingly useful in distinguishing isolated epilepsy from syndromic forms that include other clinical features such as intellectual disability, dysmorphic features, or growth delay. Discerning which syndrome a patient has can be challenging, especially when it manifests in an atypical form or the patient is young. For instance, Rett syndrome is a well-known neurodevelopmental disorder for which MECP2 was the only gene tested for many years. Now we understand that several syndromes overlap with Rett, including Angelman, Koolen-DeVries, and others.7 The Invitae syndromic neurodevelopmental epilepsy panel analyzes genes for a range of disorders in which epilepsy is one prominent feature among others.
The last base to cover is an important one in epilepsy. Increasingly, patients and their families are seeing access to drug trials that hold promise for curing or at least reducing the effects of epilepsy.8 There are a range of drugs in development for Rett syndrome, tuberous sclerosis, infantile neuronal ceroid lipofuscinosis, PCDH19-related epilepsy, and others. Identifying a molecular diagnosis via genetic testing can potentially qualify patients for these drug trials.
Fortunately, we have come a long way in understanding how epilepsy manifests clinically and robust genetic testing is now available to help patients and their families reach a diagnosis, access effective treatments, qualify for drug trials, and, in many cases, find a sense of closure. Invitae’s test for epilepsy represents an important expansion of its pediatric genetic testing menu and further enhances the company’s mission of providing high-quality affordable genetic testing to all those who need it.
1International League Against Epilepsy, www.ilae.org. Accessed November 2015.
2Epilepsy Foundation, www.epilepsy.com. Accessed November 2015.
3Pal, DK, et al., Nat Rev Neurol. 2010; 6:445-53.
4Thomas, RH and Berkovic, SF, Nat Rev Neurol. 2014; 10:283-92.
5Poduri, A, et al., Nat Rev Neurol. 2014; 10:293-9.
6Vigevano, F, et al., Epilepsia. 2013; 54:45-50.
7Tan, WH, et al., Am J Med Genet A. 2014; 164A:975-92.
8EpiPM Consortium, Lancet Neurol. 2015; pii: S1474-4422(15)00199-4.