Targeted gene panel and genotype-phenotype correlation in children with developmental and epileptic encephalopathy
Introduction
Epileptic encephalopathy refers to a group of severe pediatric epilepsies in which epileptic activities contribute to cognitive delay or regression. (Scheffer et al., 2017) Recently, developmental and epileptic encephalopathy (DEE) was introduced as a new concept, because cognitive deterioration can also derive from genetic etiologies, irrespective of epileptic activity. (Scheffer et al., 2017) With advances in sequencing methods, monogenic mutations responsible for DEE have been identified, suggesting underlying genetic etiologies in DEE patients who were previously included in the unknown etiology group. (Moller et al., 2015) Advanced sequencing methods have shortened the diagnostic process, and potential benefits from gene-based determination of clinical progression and therapeutic regimens might be expected in this era of emerging precision medicine.
Therefore, here, we sought to elaborate our single-center experience of using targeted gene-panel sequencing to diagnose the genetic etiology of DEE and to reveal the clinical implications of gene-panel studies by extensively reviewing genotype–phenotype correlations in such patients.
Section snippets
Patients
A total of 280 unrelated pediatric patients with early-onset DEE of unknown etiology were recruited from the epilepsy clinic of Severance Children’s Hospital between March 2015 and June 2017. All patients met the following criteria: (1) seizure onset before the age of 3 years; (2) multiple epileptiform discharges with severely disorganized background activity on electroencephalography (EEG); (3) progressive developmental deterioration or a known developmental and epileptic encephalopathy
Demographics and general characteristics
Among the 278 patients (268 Koreans, 1 Mongolian, and 9 Caucasians), pathogenic monogenic mutations were identified in 103 (37.1%). Thirty-five different causative genes were found, with SCN1A being the most frequent (n = 11, 10.7%), followed by CDKL5 (n = 9, 8.7%), CHD2 (n = 8, 7.8%), KCNQ2 (n = 7, 6.8%), STXBP1 (n = 7, 6.8%), SCN2A (n = 5, 4.9%), SCN8A (n = 5, 4.9%), SYNGAP1 (n = 5, 4.9%), and others (Table 1). Thirty-four (33.0%) of 103 patients with identified mutations carried variants
Discussion
We defined 35 different disease-causing monogenic mutations in 37.1% patients with DEE. These patients had a lower age at seizure onset and had more intractable seizures than patients in whom mutations were not identified with the gene panel screening.
With the advent of sequencing methods that enable sequencing of several DNA regions in a single reaction, there have been significant advances in the identification of epilepsy-related genes. (Moller et al., 2015) Monogenic epilepsy, in which a
Conclusion
Monogenic mutations, especially de novo monogenic variants, are an important underlying etiology for DEE, and targeted gene-panel sequencing is an effective diagnostic tool for DEE. The diagnostic yield is higher in drug-resistant epilepsy, and in patients with earlier seizure onset especially during the neonatal period. Although phenotypic pleiotropy exists, we could confirm correlation of genotypes with the clinical progress and seizure outcomes to specific therapeutic regimens that were
Funding
This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI15C1601) and by a faculty research grant of Yonsei University College of Medicine for 2013 (6-2013-0031) and 2015(6-2015-0140).
Conflict of interest
The authors have no conflicts of interest relevant to this article to disclose.
Acknowledgements
None.
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