Epilepsy and Seizure Plus Panel

Epilepsy is a highly heterogeneous disorder, with great variation in the age of onset, etiology, type of seizures, developmental outcome, EEG and image findings (MRI, etc), response to medication, and a wide range of comorbidities. Genetic epilepsy has a wide phenotypic spectrum, ranging from mild seizure disorders in patients with normal cognition to severe early-onset epileptic encephalopathies associated with severe developmental delay and intellectual disability. The etiology of epilepsy includes structural, genetic, infectious, metabolic, immune and unknown causes. Seizures are classified into focal onset, generalized onset, and unknown onset, while epilepsy is divided into focal, generalized, combined generalized and unknown type. An epilepsy syndrome refers to a cluster of features incorporating seizure types, together with EEG, and imaging findings (Sharma and Prasad. 2013. PubMed ID: 23250121; Wilmshurst et al. 2015. PubMed ID: 26122601; Scheffer et al. 2017. PubMed ID: 28276062; Fisher et al. 2017. PubMed ID: 28276064). Epileptic encephalopathy was recently redefined as epileptic activity itself contributing to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone. Epileptic encephalopathy can also be applied to single gene disorders, for example, CDKL5 encephalopathy and CHD2 encephalopathy. Certain disorders have been reported to be associated with developmental and epileptic encephalopathy (Scheffer et al. 2017. PubMed ID: 28276062; Hamdan et al. 2017. PubMed ID: 29100083).

This panel covers numerous well-characterized genes causative for epilepsy syndromes and non-syndromic epilepsy genes, as well as newly recognized developmental epileptic encephalopathies-related genes (Wilmshurst et al 2015. PubMed ID: 26122601; Baldassari et al. 2016. PubMed ID: 27208208; Ricos et al. 2016. PubMed ID: 26505888; Møller et al. 2016. PubMed ID: 27781031; de Kovel et al. 2016. PubMed ID: 27652284; Hildebrand et al. 2016. PubMed ID: 27029629; von Spiczak et al. 2017. PubMed ID: 28667181; Hamdan et al. 2017. PubMed ID: 29100083).

Importantly, this panel also covers following genes which are related to epilepsy treatment:

The genetic etiology of the different epilepsies is extremely heterogeneous, ranging from monogenic causes with little or no influence from modifiers or environmental factors to genetically complex forms involving multiple genes, modifier genes and environmental factors. Epilepsy/seizure disorders can be inherited in an autosomal dominant, autosomal recessive, X-linked manner or by complex inheritance. Many epilepsy/seizure cases are sporadic, occurring in families with no prior history. Sporadic cases of epilepsy/seizure are commonly caused by dominant, de novo pathogenic variants in epilepsy-related genes (Allen et al. 2013. PubMed ID: 23934111; Møller et al. 2016. PubMed ID: 27781031; Wilfert et al. 2017. PubMed ID: 29179772; Scheffer et al. 2017. PubMed ID: 28276062; Fisher et al. 2017. PubMed ID: 28276064). Mosaicism may affect the severity of epilepsy, and a genetic etiology does not exclude an environmental contribution (Scheffer et al. 2017. PubMed ID: 28276062).

See individual gene test descriptions for information on molecular biology of gene products and mutation spectra.

This panel typically provides 99.6% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

This panel includes genes causative for autosomal dominant, autosomal recessive and X-linked epilepsy and seizures. Extrapolating from previously published studies of next generation sequencing in large cohorts of patients with early infantile epileptic encephalopathy, we predict that this panel will identify pathogenic variants in about 37% of early infantile epileptic encephalopathy cases with unknown cause (Lemke et al. 2012. PubMed ID: 22612257; Wang al. 2014. PubMed ID: 24818677; Ream and Mikati. 2014. PubMed ID: 25108116). This panel should identify pathogenic variants more than 90% in Dravet syndrome patients (Carvill et al. 2014. PubMed ID: 24623842).