Background: Early onset epileptic encephalopathy (EOEE), a devastating epileptic syndrome, carries a grave prognosis. Modern genomic technologies have been proven invaluable in detecting a genetic etiology, namely a copy number variation or single gene mutation, of which nearly 90% are usually de novo.
Objectives: To confirm a genomic diagnosis in a cohort of children with EOEE.
Methods: A worldwide multicenter genomic study of pediatric severe epilepsy syndromes. Children fulfilling inclusion criteria and treated at Schneider Children`s Medical Center were recruited (since 2012). Trio samples were analyzed by targeted whole exome sequencing (WES) (21 genes).
Results: 41 children were recruited (37-simplex; 4-familial cases). Results are available for 37/41. WES or CMA identified a causative variant in 24/37 (65%): 2/24 (8%) had a pathogenic copy number variation (45 Mb Dup. Xq21.1-q25, 2.9Mb Del. 10q11.22); 22/24 (91%) had a confirmed pathogenic variant in WES, four of which were in genes not included in the targeted 21-gene list (RARS2, KCNQ1; ALDH7A1). WES identified 3 variants-of-unknown-significance in 2 known epilepsy genes (GNAO1, CDKL5) and one most likely pathogenic variant in an unknown gene in 2 siblings. WES was negative in 8 children.
De novo variants accounted for 13/24 (54%); inherited variants for 7/24 (30%). Familial studies are still ongoing in 4 cases.
Conclusions: Combined CMA and WES investigations in a cohort of EOEE confirmed a diagnosis in 65%. A relatively high proportion of mutations were inherited. This may affect reproductive choices of families. We suggest that genomic approach should be considered early in the evaluation of EOEE.
