Genetics of Epileptic Encephalopathies

Abstract

Abstract Epileptic encephalopathy (EE) is a descriptive term for a group of severe epilepsy disorders characterised predominantly by early onset drug‐resistant seizures, accompanied by developmental stagnation or regression secondary to epileptiform activity. The aetiological diagnosis of EE is challenging, as causes are numerous with significant phenotypic overlap: these include acquired causes as well as numerous de novo or inherited monogenic seizure disorders, genetic inborn errors of metabolism, intellectual disability syndromes and chromosomal aberrations. A diagnostic pathway should include consultation with a Paediatric Neurologist and Clinical Geneticist, screening for immediately treatable causes, neuroimaging and electroencephalogram (EEG) and genetic testing including chromosomal microarray and consideration of a next generation sequencing technique that can interrogate multiple genetic causes, such as a multigene panel, or exome/genome sequencing. Understanding the underlying genetic cause of EE can allow accurate genetic counselling for the family and providing personalised management and support. Key Concepts EE is a descriptive term for a group of disorders where epileptiform activity itself contributes to severe cognitive and behavioural impairments above and beyond what might be expected from the underlying pathology. Although EE can be acquired, most cases of previously considered cryptogenic EE are now recognised to be due to single gene disorders. The majority of monogenic EE are due to de novo pathogenic variants: however, up to 10% of EE may be due to X‐linked or autosomal recessive conditions, with higher rates in populations where consanguineous marriage is more common. Although there are some genotype/phenotype correlations, a single genetic cause can result in a variety of EE and non‐EE phenotypes, and each subtype of EE can have a variety of genetic causes. Genetic heterogeneity in EE limits the value of targeted genetic testing. An optimal, cost‐effective diagnostic approach involves first‐tier tests that target common and treatable conditions, followed by second‐tier tests including sequencing of a panel of genes known to cause EE or exome/whole genome sequencing to allow genome‐wide interrogation. Factors influencing choice of type of genetic test (multigene panel versus exome/genome sequencing) include epilepsy semiology, developmental regression, additional neurological or extra‐cerebral manifestations, family history and clinician and patient choice and cost. Phenotypic factors that suggest exome/genome sequencing may be valuable and include developmental regression and progressive features, multiorgan involvement including dysmorphism, additional neurological features and cerebral malformations. Evaluation of the likely pathogenicity of a novel genetic variant should include consideration of similarity with the types of genetic variants previously identified as causal of EE for that gene, including which functional domain(s) are implicated as well as overlap with the associated clinical features previously described for that condition. For variants remaining of uncertain clinical significance, ongoing pathogenicity assessment will be required in the light of advances in the understanding of the genetics of EE.