Preliminary Results of Whole Exome Sequencing in a Cohort of Sicilian Children with Early-Onset Epileptic Encephalopaty

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Objective: Early-Onset Epileptic Encephalopathies encompass a group of severe disorders characterized by refractory epilepsy and/or electroencephalographic abnormalities with progressive cerebral dysfunction. The modern technologies of molecular genetics are providing crucial diagnostic insights, however, this is only the tip of the iceberg and a great effort is still necessary to detect new genes, new mutations and define their causative role. We herein present the preliminary results in our cohort with EOEE included into extensive multicenter Whole Exome Sequencing study (SynaPs network). Methods: Twenty-four patients with electroclinical diagnosis of EOEE, no structural abnormalities at brain MRI scans and negative array-CGH were enrolled. Results: A de novo mutation on GRIN1 gene was detected in a 5-years-old girl with EOEE, severe hypotonia, pyramidal and extrapyramidal signs and Rett-like manual stereotypies. GRIN1 mutations impairs functioning of glutamate NMDA receptor. In an 8 years-old male patient with EOEE, hypotonia, ataxia and autism features, a de novo mutation in KCNA2 gene was found. It encodes for potassium channel Kv1.2 and has been associated to inherited episodic ataxia and epilepsy. In a 16 years-old boy with EOEE and subsequent Lennox-Gastaut ’s phenotype, WES analysis evidenced a damaging mutation in the contactin 2 (CNTN2) gene. A pathogenic role of CNTN2 has been hypothesized due to its interaction with Contactin-associated Protein-like 2 which is implicated in several neurological disorders. A SZT2 gene mutation was found in a 7 years-old male with EOEE, microcephaly and severe developmental delay. To date, two clinical reports described few children with SZT2 mutations and heterogeneous clinical phenotypes including epileptic encephalopathy, developmental delay and dysmorphisms. Conclusion: WES analysis may significantly enhance diagnostic chances in patients with EOEE. A synergic work between clinicians and geneticists is mandatory to assess genotype-phenotype correlation and provide proper genetic counseling. Disease- specific treatments could be attempted and taken into account in clinical practice in the future.