Epilepsy genetics is an emerging field with increasing therapeutic implications resulting from genetic findings. Despite an overall enthusiasm for precision medicine in epilepsy and other disciplines, there remains no consensus on the approach to genetic testing. A recent study by Berg et al demonstrated a relatively similar diagnostic yield of epilepsy next-generation sequencing (NGS) gene panels compared with whole-exome sequencing (27% vs 33%). Although the utility of NGS panels are consistently demonstrated to our knowledge, no study has systematically evaluated the variability in genes tested among clinically available NGS panels. We compared the potential diagnostic yield of commercially available NGS epilepsy panels to detect the genetic findings identified in a recently published cohort of early-life epilepsy.

Dr. Annapurna Poduri [a CURE grantee] and colleagues from Boston Children’s Hospital compared 10 commercially available NGS gene panels from three major vendors (Athena Diagnostics, Ambry Genetics and GeneDx).

This is the second of a 2?part primer on the genetics of the epilepsies within the Genetic Literacy Series of the Genetics Commission of the International League Against Epilepsy.

In Part 1, we covered types of genetic variation, inheritance patterns, and their relationship to disease. In Part 2, we apply these basic principles to the case of a young boy with epileptic encephalopathy and ask 3 important questions: (1) Is the gene in question an established genetic etiology for epilepsy? (2) Is the variant in this particular gene pathogenic by established variant interpretation criteria? (3) Is the variant considered causative in the clinical context? These questions are considered and then answered for the clinical case in question.

Advances in genetic testing offer new insights to parents who have a child with a rare but serious form of epilepsy, epileptic encephalopathy (EE), found in one of about every 2,000 births and characterized by developmental disabilities as well as horrible seizures.

“New ways of sequencing the human genome mean geneticists and genetic counselors have much more to say to parents who wonder if future children might carry the disease,” says Dr. Heather Mefford, associate professor of pediatrics (genetic medicine) at University of Washington School of Medicine and Deputy Scientific Director of the Brotman Baty Institute for Precision Medicine, co-senior author of findingspublished this week in the New England Journal of Medicine.

A big question from any parent of a child with EE is, “What are the odds that our other children might have this condition?” For decades, parents whose child had epilepsy were told there’s a 1 to 5 percent chance that other children might inherit the mutation. This was based on clinical evidence – the numbers of reoccurrences physicians saw in the clinic.

But armed with more precise testing, the geneticists found parental mosaicism that wasn’t easily detected before in about 10 percent of families, putting these families at higher risk of passing the mutation to another child. What this means in practical terms is that this small group probably accounts for most of the reoccurrences. For some parents, there’s good news: if this parental mosaicism was not detected, your odds of having another such child with epilepsy could be much less than 1 percent.

Summary: Epilepsy has a strong genetic component, with an ever?increasing number of disease?causing genes being discovered. Most epilepsy?causing mutations are germ line and thus present from conception. These mutations are therefore well positioned to have a deleterious impact during early development. Here [researchers] review studies that investigate the role of genetic lesions within the early developmental window, specifically focusing on genetic generalized epilepsy (GGE). Literature on the potential pathogenic role of sub?mesoscopic structural changes in GGE is also reviewed.

Evidence from rodent models of genetic epilepsy support the idea that functional and structural changes can occur in early development, leading to altered seizure susceptibility into adulthood. Both animal and human studies suggest that sub?mesoscopic structural changes occur in GGE.

The existence of sub?mesoscopic structural changes prior to seizure onset may act as biomarkers of excitability in genetic epilepsies. [Researchers] also propose that presymptomatic treatment may be essential for limiting the long?term consequences of disease?causing mutations in genetic epilepsies.

PURPOSE: This study aims to evaluate the associations between genetic polymorphisms and the effect of sodium valproate (VPA) therapy in children with generalized seizures.

METHODS: A total of 174 children with generalized seizures on VPA therapy were enrolled. Steady-state trough plasma concentrations of VPA were analyzed. Seventy-six single nucleotide polymorphisms involved in the absorption, metabolism, transport, and target receptor of VPA were identified, and their associations with the therapeutic effect (seizure reduction) were evaluated using logistic regression adjusted by various influence factors.

RESULTS: rs7668282 (UGT2B7, T?>?C, OR?=?2.67, 95% CI: 1.19 to 5.91, P?=?0.017) was more prevalent in drug-resistant patients than drug-responsive patients. rs2242480 (CYP3A4, C?>?T, OR?=?0.27, 95% CI: 0.095 to 0.79, P?=?0.017) and rs10188577 (SCN1A, T?>?C, OR?=?0.40, 95% CI: 0.17 to 0.94, P?=?0.035) were more prevalent in drug-responsive patients compared to drug-resistant patients.

CONCLUSION: In children with generalized seizures on VPA therapy, polymorphisms of UGT2B7, CYP3A4, and SCN1A genes were associated with seizure reduction. Larger studies are warranted to corroborate the results.

Researchers have discovered a “missing mutation” in severe infant epilepsy — long-suspected genetic changes that might trigger overactive, brain-damaging electrical signaling leading to seizures. They also found early indications that specific anti-seizure medications might prevent disabling brain injury by controlling epilepsy during a crucial period shortly after birth.

“These are still early days, but we may be able to use this knowledge to protect the newborn brain and improve a child’s long-term outcome,” said study leader Ethan M. Goldberg, MD, PhD, a pediatric neurologist at Children’s Hospital of Philadelphia.

Goldberg collaborated with European and American researchers in this neurogenetic study of early infantile epileptic encephalopathy, published online Feb. 21, 2018 in Annals of Neurology.

The study focused on mutations in the gene SCN3A. Scientists already knew that the gene had a pattern of high expression in the brain, before and shortly after birth. Variants in SCN3A had also been previously linked to less severe forms of epilepsy, but the current research solidified this link and was the first to establish that SCN3A mutations cause the severe infantile form.

Translating these findings into potential clinical treatments, Goldberg stressed, will require considerable further research — both in nerve cells and in future animal models, in which neurologists can test possible precision-medicine treatments for safety and efficacy before they can be investigated in patients. In addition, the current research allowed the SCN3A gene to be added to an existing diagnostic test, CHOP’s Epilepsy Panel, which uses next-generation sequencing to rapidly test for over 100 genetic causes of childhood epilepsy.

Precise, early diagnosis, added Goldberg, will be crucial, because of the highly regulated timetable of early-life neurological events. “The mutation’s activity in the Nav1.3 sodium ion channel occurs during a short period in newborns, but if we can intervene during that window, we may be able to help prevent long-term neurological injury and benefit patients,” he said.