Comparing The Diagnostic Yield and Clinical Utility of Trio-Whole Exome Sequencing and Clinical Exome Sequencing In Chil

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 542 probands (<12 years) to have well defined or unclassified phenotypes of DEE. Out of 542 probands, 150 underwent trio-WES and 27 underwent CES prior to trio-WES. Pathogenic or likely pathogenic variants (P/LP) identified in 41.1% (223/542) of our patients. 292 out of 542 had Variants of uncertain significance (VUS) and 91 out of 542 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 48.6% (73/150) which includes 30.6% de novo variants and 6% of variants with homozygous recessive and 5.3% of compound heterozygous pattern of inheritance. For 27 patients who underwent CES prior to trio-WES, trio-WES was able to identify 33.3% of the P/LP variations, whereas CES could only achieve a diagnostic yield of 11.1%. 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 to 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 aetiology of patients with unknown causes of DEE.