Customized targeted massively parallel sequencing enables the identification of novel pathogenic variants in Tunisian patients with Developmental and Epileptic Encephalopathy

Abstract

Background Developmental and Epileptic Encephalopathies stand for a heterogenous group of epileptic syndromes, where the epileptic activity itself and/or the etiology contribute to cognitive and behavioral impairment. In recent decades, genetic etiology has increasingly been recognized as the cause of Developmental and Epileptic Encephalopathies and numerous genes have been identified, thanks to advances in genetic technologies. These discoveries have enabled precision treatments for several syndromes. Therefore, the identification of the causal variant in a gene is an intrinsic starting point to specify a precision therapy for the patient and an adequate management. Results We developed a custom panel for Next Generation Sequencing of the coding sequences of 116 genes in individuals with Developmental and Epileptic Encephalopathy from the Tunisian population. Segregation analyses as well as in silico studies have been conducted to assess the identified variants’ pathogenicity. We report 12 pathogenic variants in SCN1A, CHD2, CDKL5, SZT2, KCNT1, GNAO1, PCDH19, MECP2, GRIN2A, and SYNGAP1 in patients with Developmental and Epileptic Encephalopathy. Five of these variants are novel: “c.149delA, p.(Asn50MetfsTer26)” in CDKL5; “c.3616C>T, p.(Arg1206Ter)” in SZT2; “c.111_113del, p.(Leu39del)” in GNAO1; “c.1435G>C , p.(Asp479His)” in PCDH19; as well as “c.2143delC, p. (Arg716GlyfsTer10)”in SYNGAP1. Additionally, for five of our patients, the genetic result facilitated the choice of the appropriate treatment. Conclusion This is the first report of a custom gene panel to identify genetic variants implicated in Developmental and Epileptic Encephalopathy in the Tunisian population as well as the North African region (Tunisia, Egypt, Libya, Algeria, Morocco) with a diagnostic rate of 30%. This high-throughput sequencing panel has considerably improved the rate of positive diagnosis of Developmental and Epileptic Encephalopathy in the Tunisian population, which was less than 15% using Sanger sequencing. The benefit of genetic testing in these patients was approved by both physicians and parents.