Genomic testing for epilepsy 333 genes NGS panel

Epilepsy is defined by the appearance of at least two unprovoked seizures occurring with at least 24 hours difference. It is a relatively common neurological disorder, affecting at least 0.8% of the population. The International League Against Epilepsy classifies seizures into two main categories:

• Generalized seizures, involving both cerebral hemispheres. For example, tonic-clonic, myoclonic, clonic, tonic and atonic seizures are some of the types of generalized seizures.
• Focal seizures, derived from neural networks of a single hemisphere of the brain. Traditionally, focal seizures are classified as ‘simple focal epileptic seizures’, which do not result in loss of consciousness, and “complex focal epileptic seizures” that cause a change in behavior and/or loss of conscience.

Certain types of seizures, including infantile spasms, do not belong to any of the above categories and remain unclassified.

Epilepsy may be due to a genetic disease, trauma or infection as well as structural abnormalities in the brain, though in many cases the exact cause is not known. Genetic causes are the basis for approximately 40% of patients and several genes have been identified that cause both generalized seizures and focal seizures as well as non-classified types of epilepsy, including infantile spasms.

The genetic etiology of idiopathic generalized epilepsy is often complicated, as it is often due to a combination of many genetic factors each contributing a small risk for epilepsy and these risks can be further modified by environmental factors.

We now know that approximately 2% of patients with idiopathic generalized epilepsy harbor a mutation in a gene associated with inherited epilepsy. However, the proportion of patients with inherited epilepsy is higher for certain types of epilepsy, including infantile spasms and benign familial neonatal epilepsy.

he mode of inheritance may be autosomal dominant, autosomal recessive or X-linked. Similarly, mutations in a single gene may be associated with different types of seizures (clinical heterogeneity) and conversely, mutations in different genes can cause the same phenotype of epilepsy (genetic heterogeneity).

Furthermore, epilepsy may be a single neurological symptom or may manifest in conjunction with other neurological symptoms or diseases. Finally, several genetic syndromes, such as West syndrome, Ohtahara syndrome or Lennox-Gastaut syndrome, and others, include epilepsy as a clinical symptom.

Seizures may be limited in time or not, and are typically managed through medication. In some cases, however, people with epileptic encephalopathy have frequent seizures that do not respond to treatment and lead to serious health issues.

Genomic testing for epilepsy aims to accurately and effectively identify the underlying genetic causes, particularly useful:

• for the diagnosis of the particular type of epilepsy
• for the prediction of disease progression,
• for determining the appropriate medication and disease management, and
• for the prevention of disease in the extended family.

In general, identification of the precise mechanism leading to the expression of epilepsy through genetic testing undoubtedly facilitates the development and introduction of new and personalized treatments.

Recently, the introduction of Next Generation Sequencing (NGS) technology has become a highly effective diagnostic strategy, through the parallel analysis of a large number of genes involved all types of genetic diseases affecting the eyes.

InterGenetics has developed and offers an NGS panel for the genomic analysis of ~333 genes (see list of genes) which have been associated with the occurrence of all known forms of epilepsy, regardless of the mode of inheritance. Many of the genes encode ion channels, involved in stabilization or propagation of neuronal activity, other genes code for neuro-transmitters and receptors, while other genes are associated with syndromic forms of the disease.

We perform DNA sequence analysis, via Next Generation Sequencing (NGS) on a Genome Analyzer – Ion Proton platform, of all exons and intron-exon junctions/splice sites of the 333 genes, allowing us to detect >98% of all pathogenic mutations of the genes through the use of specially developed bioinformatics tools, thus providing in a single step an increased clinical sensitivity and performance compared to single gene testing.

Where possible and/or necessary, we carry out additional MLPA analysis in order to detect deletions/duplications of the genes (please consult the final test report).

The test is highly sensitive and complex, so it is necessary that the results are assessed by a specialized team of clinical and molecular geneticists, in order to ensure safe and reliable testing.

Proper clinical genetic assessment and genetic counseling, both before and after testing, is essential in order to determine the optimum testing strategy and also to communicate properly the concepts of pathological and normal.