A real-world comparison between the diagnostic yield of trio-whole exome sequencing and proband-only targeted exome sequencing in complex childhood epilepsy.

Objective: Exome sequencing is the preferred method for the molecular diagnosis of childhood drug-resistant epilepsies (DRE) of uncertain etiology, particularly the developmental and epileptic encephalopathies (DEE) with a challenge being genotype-phenotype heterogeneity. This study assesses the diagnostic utility of trio-whole exome sequencing (trio-WES) over a panel-based targeted exome sequencing (TES).

Methods: We performed genetic testing in 400 probands (age of onset <12 years) who had been diagnosed with complex pediatric epilepsy syndromes (refractory focal/generalized epilepsies of uncertain etiology and DEE). Among the 400 probands, 158 underwent trio-WES and 242 underwent TES.

Results: The overall yield of pathogenic/likely pathogenic variants was similar, at 42.1 % for 242 patients who underwent TES and 42.4 % for 158 patients with trio-WES. However, among 67 disease causing variants identified by trio-WES, 67.2 % were established as de novo at baseline evaluation. A major highlight is that trio-WES achieved a diagnosis in 10 (35.7 %) of 28 patients with inconclusive/negative TES. The cost analysis shows that trio-WES ($534) is probably the more cost-effective method in early childhood wherein de novo pathogenic variants are likely to be causative, as ordering it after negative or inconclusive TES results will have an added cost.

Conclusions: This study demonstrates real world utility of trio-WES as a useful and cost-efficient tool for determining de novo genetic etiologies for unexplained childhood DRE phenotypes.