Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice.
Ingrid E Scheffer, Caitlin A Bennett, Deepak Gill and 6 others
PMID 35701389WHAT IT FOUND
Exome sequencing found a genetic cause in 36 of 103 children with severe epilepsy, rising to 41% if seizures started before age 2.
In 13 of those 36 diagnosed cases, the result changed medical management, such as choosing specific seizure drugs or stopping ones that made seizures worse.
Key findings
01A genetic cause was identified in 36 of 103 patients (35%), with higher yield in those with seizure onset under 2 years (41%) compared to older onset (18%).
02For 13 of the 36 patients with an identified genetic cause, the diagnosis had direct management implications, including choosing specific antiseizure medications or screening for complications.
03Parental mosaicism was found in one mother who was 10.5% mosaic for the pathogenic variant, highlighting a recurrence risk for future pregnancies even when parents appear unaffected.
STILL TO COME
How it was doneWhat they found
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What it does not show
The study excluded children with static intellectual disability and epilepsy without developmental regression, so it does not apply to all patients with epilepsy and cognitive issues. The yield of 35% means the majority of patients (65%) still did not receive a genetic diagnosis, leaving their cause unknown. Reclassification of variants and detection of CNVs occurred over time using newer technologies (high-density microarrays) that were not available for all patients at the start, suggesting the diagnostic yield might be higher if these methods were used universally. The study did not include genome sequencing, which might identify intronic variants or repeat expansions missed by exome sequencing.
Declared interests
Funded by the Australian Genomics Health Alliance. The authors declare no conflicts of interest.
The easy way to misread this
Do not assume a negative exome result rules out a genetic cause. In this study, six patients initially thought to have no diagnosis or uncertain variants were later found to have pathogenic causes through reanalysis, new technologies, or updated literature. A negative result today may not be negative in two years.