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

Abstract

Purpose

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.

Conclusion

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.