Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients

Abstract

BackgroundMany genes are candidates for involvement in epileptic encephalopathy (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional evidence exists for a definite annotation.MethodsTo increase the number of validated EE genes, we sequenced 26 known and 351 candidate genes for EE in 360 patients. Variants in 25 genes known to be involved in EE or related phenotypes were followed up in 41 patients. We prioritized the candidate genes, and followed up 31 variants in this prioritized subset of candidate genes.ResultsTwenty‐nine genotypes in known genes for EE (19) or related diseases (10), dominant as well as recessive or X‐linked, were classified as likely pathogenic variants. Among those, likely pathogenic de novo variants were found in EE genes that act dominantly, including the recently identified genes EEF1A2, KCNB1 and the X‐linked gene IQSEC2. A de novo frameshift variant in candidate gene HNRNPU was the only de novo variant found among the followed‐up candidate genes, and the patient's phenotype was similar to a few recent publications.ConclusionMutations in genes described in OMIM as, for example, intellectual disability gene can lead to phenotypes that get classified as EE in the clinic. We confirmed existing literature reports that de novo loss‐of‐function HNRNPUmutations lead to severe developmental delay and febrile seizures in the first year of life.

Novel mutations and phenotypes of epilepsy‐associated genes in epileptic encephalopathies

“…SPTAN1 had been reported to be a causative gene for West syndrome and the reported mutations were in‐frame deletion or insertion . A missense mutation was recently reported in a patient with early infantile epileptic encephalopathy . The missense mutation R1054H presented at a low MAF and was predicted to be damaging by MutationTaster.…”

Genotype and phenotype analysis using an epilepsy‐associated gene panel in Chinese pediatric epilepsy patients

“…Genetic pathogenic variants have been identified as the most important factors in epilepsy syndromes. Hence, targeted genetic sequencing studies have been extensively and intensively applied in epilepsy syndromes, especially epileptic encephalopathy (EE) in infants . It also remains important to evaluate the genetic etiology of epilepsy cases that occur in subjects with no known family history who were therefore previously considered idiopathic.…”

The importance of dynamic re-analysis in diagnostic whole exome sequencing

“…Inspection of recent literature9 indicates that a de novo splice-acceptor mutation in HNRNPU in patient 6 that was classified as an ‘interesting finding' in the original report can now be considered to be a likely cause of (at least) the patient's epilepsy and intellectual disability.…”