Epilepsy is a group of disorders characterized by recurrent seizures, and is one of the most common neurological conditions. The genetic basis of epilepsy is clear from epidemiological studies and from rare gene discoveries in large families. The three major classes of epilepsy disorders are genetic generalized, focal and encephalopathic epilepsies, with several specific disorders within each class. Advances in genomic technologies that facilitate genome-wide discovery of both common and rare variants have led to a rapid increase in our understanding of epilepsy genetics. Copy number variant and genome-wide association studies have contributed to our understanding of the complex genetic architecture of generalized epilepsy, while genetic insights into the focal epilepsies and epileptic encephalopathies have come primarily from exome sequencing. It is increasingly clear that epilepsy is genetically heterogeneous, and novel gene discoveries have moved the field beyond the known contribution of ion channels to implicate chromatin remodeling, transcriptional regulation and regulation of the mammalian target of rapamycin (mTOR) protein in the etiology of epilepsy. Such discoveries pave the way for new therapeutics, some of which are already being studied. In this review, we discuss the rapid pace of gene discovery in epilepsy, as facilitated by genomic technologies, and highlight several novel genes and potential therapies.

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Advancing epilepsy genetics in the genomic era

Technological advances have paved the way for accelerated genomic discovery and are bringing precision medicine clearly into view. Epilepsy research in particular is well suited to serve as a model for the development and deployment of targeted therapeutics in precision medicine because of the rapidly expanding genetic knowledge base in epilepsy, the availability of good in-vitro and in-vivo model systems to efficiently study the biological consequences of genetic mutations, the ability to turn these models into effective drug-screening platforms, and the establishment of collaborative research groups. Moving forward, it is crucial that these collaborations are strengthened, particularly through integrated research platforms, to provide robust analyses both for accurate personal genome analysis and gene and drug discovery. Similarly, the implementation of clinical trial networks will allow the expansion of patient sample populations with genetically defined epilepsy so that drug discovery can be translated into clinical practice.

A roadmap for precision medicine in the epilepsies

Targeted resequencing gene panels are used in the diagnostic setting to identify gene defects in epilepsy. We performed targeted resequencing using a 30-genes panel and a 95-genes panel in 349 patients with drug-resistant epilepsies beginning in the first years of life. We identified 71 pathogenic variants, 42 of which novel, in 30 genes, corresponding to 20.3% of the probands. In 66% of mutation positive patients seizures onset occurred before age 6 months. The 95-genes panel allowed a genetic diagnosis in 22 (6.3%) patients that would have otherwise been missed using the 30-gene panel. About 50% of mutations were identified in genes coding for sodium and potassium channel components. SCN2A was the most frequently mutated gene followed by SCN1A, KCNQ2, STXBP1, SCN8A, CDKL5 and MECP2. Twenty-nine mutations were identified in 23 additional genes, most of them recently associated with epilepsy. Our data show that panels targeting about 100 genes represent the best cost-effective diagnostic option in pediatric drug-resistant epilepsies. They enable molecular diagnosis of atypical phenotypes, allowing to broaden phenotype-genotype correlations. Molecular diagnosis might influence patient's management and translate into better and specific treatment recommendations in some conditions.

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Diagnostic Targeted Resequencing in 349 Patients with Drug‐Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes

Identifying the underlying causes of disease requires accurate interpretation of genetic variants. Current methods ineffectively capture pathogenic non-coding variants in genic regions, resulting in overlooking synonymous and intronic variants when searching for disease risk. Here we present the Transcript-inferred Pathogenicity (TraP) score, which uses sequence context alterations to reliably identify non-coding variation that causes disease. High TraP scores single out extremely rare variants with lower minor allele frequencies than missense variants. TraP accurately distinguishes known pathogenic and benign variants in synonymous (AUC = 0.88) and intronic (AUC = 0.83) public datasets, dismissing benign variants with exceptionally high specificity. TraP analysis of 843 exomes from epilepsy family trios identifies synonymous variants in known epilepsy genes, thus pinpointing risk factors of disease from non-coding sequence data. TraP outperforms leading methods in identifying non-coding variants that are pathogenic and is therefore a valuable tool for use in gene discovery and the interpretation of personal genomes.While non-coding synonymous and intronic variants are often not under strong selective constraint, they can be pathogenic through affecting splicing or transcription. Here, the authors develop a score that uses sequence context alterations to predict pathogenicity of synonymous and non-coding genetic variants, and provide a web server of pre-computed scores.

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Annotating pathogenic non-coding variants in genic regions

Lennox–Gastaut syndrome (LGS) is a severe epileptic and developmental encephalopathy that is associated with a high rate of morbidity and mortality. It is characterized by multiple seizure types, abnormal electroencephalographic features, and intellectual disability. Although intellectual disability and associated behavioral problems are characteristic of LGS, they are not necessarily present at its outset and are therefore not part of its diagnostic criteria. LGS is typically treated with a variety of pharmacological and non-pharmacological therapies, often in combination. Management and treatment decisions can be challenging, due to the multiple seizure types and comorbidities associated with the condition. A panel of five epileptologists met to discuss consensus recommendations for LGS management, based on the latest available evidence from literature review and clinical experience. Treatment algorithms were formulated. Current evidence favors the continued use of sodium valproate (VPA) as the first-line treatment for patients with newly diagnosed de novo LGS. If VPA is ineffective alone, evidence supports lamotrigine, or subsequently rufinamide, as adjunctive therapy. If seizure control remains inadequate, the choice of next adjunctive antiepileptic drug (AED) should be discussed with the patient/parent/caregiver/clinical team, as current evidence is limited. Non-pharmacological therapies, including resective surgery, the ketogenic diet, vagus nerve stimulation, and callosotomy, should be considered for use alongside AED therapy from the outset of treatment. For patients with LGS that has evolved from another type of epilepsy who are already being treated with an AED other than VPA, VPA therapy should be considered if not trialed previously. Thereafter, the approach for a de novo patient should be followed. Where possible, no more than two AEDs should be used concomitantly. Patients with established LGS should undergo review by a neurologist specialized in epilepsy on at least an annual basis, including a thorough reassessment of their diagnosis and treatment plan. Clinicians should always be vigilant to the possibility of treatable etiologies and alert to the possibility that a patient’s diagnosis may change, since the seizure types and electroencephalographic features that characterize LGS evolve over time. To date, available treatments are unlikely to lead to seizure remission in the majority of patients and therefore the primary focus of treatment should always be optimization of learning, behavioral management, and overall quality of life.

http://diposit.ub.edu/dspace/bitstream/2445/124261/1/CrossJH.pdf

Expert Opinion on the Management of Lennox–Gastaut Syndrome: Treatment Algorithms and Practical Considerations

The epileptic encephalopathies (EEs) are a devastating group of epilepsies in which epileptic activity and seizures contribute to cognitive impairment or regression.1 Most EEs begin in infancy or early childhood and are associated with poor developmental outcome. Although the cause is unknown in the majority of cases, recent studies confirm that de novo mutations and copy number variants (CNVs) play an important role.2, 3 We recently reported exome sequencing data in 264 parent–proband trios with infantile spasms (n = 149) or Lennox–Gastaut syndrome (LGS; n = 115) without syndromic features or magnetic resonance imaging (MRI) abnormalities from the Epilepsy Phenome/Genome Project (EPGP) cohort, identifying likely pathogenic, de novo sequence changes in >10% of patients.2 Here we report results of copy number analysis derived from the exome data of this cohort and 85 additional patients to further elucidate the genetic architecture of these paradigmatic EEs. Our exome‐based CNV calling yields similar results to array‐based studies for confirmed, de novo, likely pathogenic CNVs.

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Epilepsy Phenome

Papers

Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy