CLINICAL APPROACH TO GENETIC EPILEPSIES IN CHILDREN

Epilepsy is the most common neurologic disorder in pediatric age with an incidence of about 70 per 100.000 cases in children under the age of 2 . The complex landscape of genetic etiologies of epilepsies was largely expanded in the last decades2. About 5000 genes with a presumed pathogenic role and more than 150 genes with a known associated clinical phenotype were reported in the literature (about 30% of the whole diagnosed epilepsies) . Most of the genetic epilepsies were prominently studied in subjects in which an early or very early onset of seizures and a very severe developmental and neurological impairment occurred , . Other common associated clinical presentations include facial dysmorphisms, abnormalities of head circumference (mainly microcephaly), movement disorders and malformations in other organs such as heart, eye or kidney . In this context, OMIM database currently reports 67 disorders caused by single gene mutations and classified as “early infantile epileptic encephalopathies” (Table 1-https://www.ncbi.nlm.nih.gov/omim). Most of the reported genes encodes for ion channels subunits, membrane receptors/ transporters and proteins involved in the transduction of neuronal signaling or enzymes of the intermediate metabolism (Fig. 1)3,4. Pathogenic mutations in these genes result in dysfunctions in different stages of neuronal development and functioning, including synaptogenesis, pruning, neuronal migration and differentiation, neurotransmitter synthesis and release3, 4. Epilepsy phenotypes and severity, degree of developmental impairment, concurrent neurological and non neurological manifestations are extremely variable according to the functions of the different involved genes and their role in epileptogenic mechanisms4. Several studies also evidenced a remarkable heterogeneity in terms of different clinical conditions resulting from variants of the same genes (i.e.SCN2A causes both familial benign neonatal infantile epilepsy and a severe epileptic encephalopathy; KCNQ2 was initially associated with familial benign neonatal seizures and, subsequently, with an early onset epileptic encephalopathy) or similar clinical syndromes caused by different genes (i.e. Dravet syndrome can be caused by pathogenic variants in SCN1A , PCDH 19, STXBP1 or GABRA1) Next generation sequencing (NGS) includes different techniques that allow a simultaneous sequencing of exons belonging to a selected group of genes organized in panels (gene panels) or to the whole exome or genome2. Whole-exome sequencing (WES) involves the encoding part of the human genome (about 20,000 disease causing genes)2. WES analysis identifies the profile of the detected gene variants and subsequently a comparison with the polymorphic (non pathogenic) variants, distributed in the general population, is realized to identify the possible pathogenic variants . The putative pathogenic mutations are subsequently characterized in terms of de novo occurrence (variant absent in the parents) and state of homozygosity (both gene copies suffering from the same mutation) or compound heterozygous (two different mutations in the same gene )6. Whole genome sequencing (WGS) involves both the encoding and non encoding human genome2. The three groups of NGS investigations (gene panels, WES and WGS) do not identify non-coding regulatory sequences and deletions/duplications of exons that can be studied through array CGH and other cytogenetic techniques.