Genome sequencing boosts diagnostic yield for the developmental and epileptic encephalopathies

Although most developmental and epileptic encephalopathies (DEEs) have a monogenic aetiology, routine clinical genetic testing is negative for 50% of patients. We hypothesized that the diagnostic yield could be increased in a large cohort of individuals with unsolved DEEs by applying genome sequencing along with enhanced variant analyses outside of coding regions.

We performed genome sequencing for 242 participants with DEEs negative on prior genetic testing. We interrogated single nucleotide variants (SNVs), indels, and structural variants in both established and candidate DEE genes. All variants of interest were reviewed, classified, and validated by a multidisciplinary team.

A molecular diagnosis was discovered for 36/242 (15%) participants. The pathogenic or likely pathogenic variants comprised 26 SNVs and indels within coding regions, 9 structural variants, and 5 SNVs and indels in introns or non-coding genes. Variants of uncertain significance were detected in a further 10/242 (4%) participants.

Genetic diagnostic yield for individuals with unsolved DEEs improves with genome sequencing analysis. This increase reflects both the identification of structural and non-coding variants not detectable on exome or gene panel analysis, and the detection of variants in genes newly associated with DEEs.