Diagnostic yield in epileptic encephalopathies is improved by genome sequencing and re-analysis

Objective: To assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE).

Methods: We performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray (CMA), and either research ES (n=15) or diagnostic MGP (n=15).

Results: 8 diagnoses were made in the 15 individuals who received prior ES (53%): 3 individuals had complex structural variants; 5 had ES-detectable variants which now had additional evidence for pathogenicity. 11 diagnoses were made in the 15 MGP-negative individuals (68%); the majority (n=10) involved genes not included in the panel, particularly in individuals with post-neonatal onset of seizures and those with more complex presentations including movement disorders, dysmorphic features and/or multi-organ involvement.  42% of diagnoses were ...