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

Abstract

AbstractObjectiveTo develop a high throughput sequencing panel for the diagnosis of developmental and epileptic encephalopathy in Tunisia and to clarify the frequency of disease‐causing genes in this region.MethodsWe 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.ResultsWe 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 four of our patients, the genetic result facilitated the choice of the appropriate treatment.SignificanceThis 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.