Elsevier

Epilepsy Research

Volume 141, March 2018, Pages 48-55
Epilepsy Research

Targeted gene panel and genotype-phenotype correlation in children with developmental and epileptic encephalopathy

https://doi.org/10.1016/j.eplepsyres.2018.02.003Get rights and content

Highlights

  • Monogenic mutations constitute substantial etiology for developmental and epileptic encephalopathy (DEE).

  • Targeted gene panel study is an effective genetic diagnostic tool for DEE.

  • The diagnostic yield increases in patients with earlier seizure onset age, or with drug-resistant epilepsy.

  • Despite phenotypic pleiotropy, there is some clinical consistency in patients with the same genotypes.

Abstract

Objective

We performed targeted gene-panel sequencing for children with developmental and epileptic encephalopathy (DEE) and evaluated the clinical implications of genotype–phenotype correlations.

Methods

We assessed 278 children with DEE using a customized gene panel that included 172 genes, and extensively reviewed their clinical characteristics, including therapeutic efficacy, according to genotype.

Results

In 103 (37.1%) of the 278 patients with DEE, 35 different disease-causing monogenic mutations were identified. The diagnostic yield was higher among patients who were younger at seizure onset, especially those whose seizures started during the neonatal period, and in patients with drug-resistant epilepsy. According to epilepsy syndromes, the diagnostic yield was the highest among patients with West syndrome (WS) with a history of neonatal seizures and mutations in KCNQ2 and STXBP1 were most frequently identified. On the basis of genotypes, we evaluated the clinical progression and seizure outcomes with specific therapeutic regimens; these were similar to those reported previously. In particular, sodium channel blockers were effective in patients with mutations in KCNQ2 and SCN2A in infancy, as well as SCN8A, and interestingly, the ketogenic diet also showed diverse efficacy for patients with SCN1A, CDKL5, KCNQ2, STXBP1, and SCN2A mutations. Unfortunately, quinidine was not effective in 2 patients with migrating focal epilepsy in infancy related to KCNT1 mutations.

Conclusion

Targeted gene-panel sequencing is a useful diagnostic tool for DEE in children, and genotype–phenotype correlations are helpful in anticipating the clinical progression and treatment efficacy among these patients.

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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