Featuring the work of par CURE-Grantee Dr. Annapruna Poduri

Objective: This research team evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well-phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology.

Methods: The team identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection-related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. The team analyzed WES data and compared the yield in participants with and without prior clinical genetic testing.

Results: Overall, the researchers identified pathogenic or likely pathogenic variants in 40% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy-related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26% (23/90). Of the 67 participants whose molecular diagnoses were “unsolved” through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25%).

Significance: The data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well-phenotyped patients with epilepsy leads to a broader understanding of gene-specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease-associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.

BioMarin Pharmaceutical Inc. and Invitae Corporation announced that Biogen, Encoded Therapeutics, Neurogene, Praxis Precision Medicines, and PTC Therapeutics joined Behind the Seizure®, an innovative, cross-company collaboration that aims to provide faster diagnosis for young children with epilepsy. The program will also be expanded to make no-charge testing available for healthcare providers to order for any child under the age of eight who has an unprovoked seizure.

“Behind the Seizure is one of the longest-running cross-company collaborations aimed at increasing access to genetic testing. It has been shown to decrease time to diagnosis for children experiencing unprovoked seizures by one to two years from reported averages, and as more companies have joined the program, more children have been helped,” said Robert Nussbaum, chief medical officer of Invitae. “Earlier diagnosis enables clinicians to focus on providing disease-specific care sooner, which is particularly important in neurodegenerative diseases. We applaud these companies for their commitment to expanding this unique effort to help children.”

Pathogenic variants in the SCN2A gene are associated with a variety of neurodevelopmental phenotypes, defined in recent years through multicenter collaboration. Phenotypes include benign (self-limited) neonatal and infantile epilepsy and more severe developmental and epileptic encephalopathies also presenting in early infancy.

There is increasing evidence that an important phenotype linked to the gene is autism and intellectual disability without epilepsy or with rare seizures in later childhood. Other associations of SCN2A include the movement disorders chorea and episodic ataxia. It is likely that as genetic testing enters mainstream practice that new phenotypic associations will be identified. Some missense, gain of function variants tend to present in early infancy with epilepsy, whereas other missense or truncating, loss of function variants present with later-onset epilepsies or intellectual disability only. Knowledge of both mutation type and functional consequences can guide precision therapy. Sodium channel blockers may be effective antiepileptic medications in gain of function, neonatal and infantile presentations.

Key Points

• SCN2A-related disorders can present with epilepsy and/or intellectual disability with autism
• Mutation type and associated functional effects (gain vs loss of function) may predict phenotype and medication response
• Sodium channel blockers may be effective in early onset cases associated with gain of function mutations
• Insights into SCN2A-related functional effects offer a target for novel specific therapies

At what point in the course of chronic epilepsy is finding the etiology no longer worthwhile? Is it fair to assume there comes a point where knowing the cause is no longer beneficial to the patient? If that time exists, is it the medical equivalent of waving the white flag?

Understanding the genetic basis of epilepsy has changed the way treatment is delivered, particularly for patients with epileptic encephalopathies. For the majority of people with seizures, regardless of severity, understanding the etiology of their epilepsy brings an end to the diagnostic odyssey that for many has included years of testing and uncertainties about the future. Multigene panels and whole-exome sequencing have primarily been used in pediatric populations where the downstream value of accurate diagnosis is likely highest and programs providing free testing make the early identification of syndromes where the course of treatment may be altered easier. Genetic testing has particularly high yield for children with early-life epilepsy and epileptic encephalopathies where the diagnostic hit rate can exceed 25%, approaching the yield of imaging and surpassing that of metabolic testing. Unfortunately, for adults with chronic epilepsy of childhood onset, the bus has often left the station, and they are not afforded the same advances in gene testing. The question is whether that matters and the answer is we don’t really know.

The limited use of genetic testing in adults is likely multifactorial. Essentially, all of the genetic epileptic encephalopathies have onset in childhood where the majority of research interest in diagnosis and treatment of these disorders exists. Unfortunately, this fails to acknowledge the undiagnosed adult patients who could benefit if afforded the same advances in treatment. For many of these conditions, early mortality has been the rule, thus many may consider testing low yield in older individuals. However, most of these conditions represent a phenotypic spectrum that is only now becoming more obvious as increasing numbers of individuals are diagnosed, thus we truly have no handle on the number of individuals with more favorable courses. Many adults with epilepsy and intellectual disabilities may no longer have strong advocates in the search for a diagnosis as they would have had as children, thus no voice to push for genetic testing. Finally, many question whether the outcome is altered in an adult who has suffered so many years with these conditions. This is a question that will remain unanswered if we don’t identify adults living with these disorders now. Ultimately, the goal of care should likely be to decrease the burden of disease for every individual with epilepsy and having a precise diagnosis to provide the most effective care would be the obvious path to consider.

Researchers from the Walter and Eliza Hall Institute have contributed to a decades-long global effort that has revealed two new gene mutations that cause a rare type of epilepsy, familial adult myoclonic epilepsy.

The Institute research team also traced one genetic mutation back to its origin; an individual with the spontaneous mutation who lived more than 5000 years ago. The team developed technologies that can detect the specific mutations – called repeat expansions – even in small sample groups, and the tools to trace the ancestry of a mutation to its origin.

The discoveries were published in back-to-back papers in Nature Communications. Dr Mark Bennett, Dr Haloom Rafehi and Professor Melanie Bahlo from the Institute were part of the international consortium, which included clinicians, bioinformaticians and biologists from Australia, Germany, France and the Netherlands.