Genetic Diagnosis and Personalized Medicine for Patients With Epilepsy

Identification of the genetic cause in patients with clinically probable genetic epilepsy using WES

Background Epilepsy is a common neurological disorder. It affects 50 million people worldwide
 and has the highest incidence in pediatric age. According to the latest classification of the
 ILAE (International League against Epilepsy), epilepsies are divided into lesional
 (symptomatic) and non-lesional/genetic forms. Symptomatic causes of epilepsy may include
 scarring, tumors, strokes, and brain developmental disorders such as dysplasias. In
 approximately 30% of epilepsies a genetic cause of epilepsy can be hypothesized. Since the
 identification of the first epilepsy gene in 1995, over the next 25 years over 500 genes
 associated with epilepsy have been identified. The importance of many genes and many gene
 variants identified in many genes is not yet clear and the mutations identified in different
 genes require confirmation with functional studies and confirmation on larger series of
 patients. Furthermore, the genetic defect underlying many patients with epilepsy remains
 unknown to this day, despite a high level of gene sequencing effort.
 
 Molecular studies on these genes have demonstrated how pathogenic variants on these genes
 determine a protein dysfunction that can cause neuronal hyperexcitability and pathological
 synchronization of neuronal networks leading to epileptic seizures and brain dysfunction. A
 notable complication in the field of epilepsy genetics is represented by the fact that the
 concept of a gene/a disease is valid only in a few cases, as there is a high phenotypic and
 genotypic heterogeneity so that a gene can present different types of epilepsy even within
 the same family. This means that there is a complex multigenic and multifactorial genetic
 substrate for which the impact of a specific genetic variant is conditioned by variants of
 other genes. This concept is particularly valid for the most common epileptic forms such as
 idiopathic generalized epilepsies.
 
 The integration of genetic analysis with epileptological characterization in clinical
 practice is increasingly crucial in defining a clear molecular diagnosis in patients whose
 disease cause would otherwise remain unknown, and potentially allows avoiding other
 unnecessary diagnostic investigations. It is therefore expected that this will lead to
 optimizing clinical management and reducing overall costs over time. The genetic finding can
 constitute a useful biomarker for defining the outcome of the disease and for guiding
 clinical decisions such as the best choice of therapy. Despite the advantages, before
 starting the genetic testing process, patients and their family members should be informed
 about the ethical issues that may arise from genetic testing, the technical limitations,
 legal aspects and costs of genetic investigation.
 
 Aim of the study Characterization of patients with epilepsy recruited at the Hospital
 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico in Milan (Italy) and analysis with
 exome NGS sequencing of patients with the highest probability of genetic diagnosis with exome
 (use of a probability score)
 
 Endpoints of study are the following:
 
 1. Identification of the genetic cause of the forms of genetic epilepsies with the highest
 probability of molecular diagnosis with exome
 
 2. Clinical-instrumental and epileptological characterization according to the ILAE
 classification of patients with epilepsy followed at the Fondazione IRCCS Ca' Granda
 Fondazione Ospedale Maggiore Policlinico
 
 3. Correlation of clinical and instrumental parameters (in particular EEG and
 neuropsychological) of epilepsy recorded on the database with etiology, outcome and
 response to therapy