AP-6 Diagnostic Yield of Trio-Whole Exome Sequencing and Clinical Exome Sequencing in Children with Developmental and Epileptic Encephalopathy

Exome sequencing is the preferred method for the molecular diagnosis of developmental and epileptic encephalopathies (DEE) due to their distinct clinical and genetic variability. The aim of this study is to assess the clinical utility and cost-effectiveness of whole exome sequencing (WES) over targeted or clinical exome sequencing (CES). We performed WES/CES in 492 probands (<12 years) to have well-defined or unclassified phenotypes of DEE. Out of 492 probands, 114 underwent trio-WES and 26 underwent CES prior to trio-WES. Pathogenic or likely pathogenic variants (P/LP) identified in 39% (193/492) of our patients. 159 out of 492 had variants of uncertain significance (VUS) and 140 out of 492 had no potentially disease causing variants identified. The diagnostic yield of CES was 40.1% without performing the parental segregation. Trio-WES revealed a diagnostic yield of 27.19% which includes 24.5% de novo variants and 5.26% of variants with homozygous recessive and compound heterozygous pattern of inheritance. For 26 out of 125 patients who underwent CES prior to trio-WES, trio-WES was able to identify 30.7% of the P/LP variations, whereas CES could only achieve a diagnostic yield of 7.69%. The cost comparison analysis revealed that Trio-WES (`45000) is the preferred cost-effective method for first-tier assessment as it has the better diagnostic yield when compared with CES and trio-WES after negative CES results in an additional cost of `13000. This study substantiates the utility of trio-WES as a useful diagnostic and cost effective tool in determining the etiology of patients with unknown causes of DEE. Publication History Article published online: 12 September 2024 © 2023. Indian Epilepsy Society. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India