Impact on Clinical Decision Making of Next-generation Sequencing (NGS) in Pediatric Epilepsy in a Tertiary Epilepsy Referral Center

Objectives: Next-generation sequencing (NGS) helps to identify many monogenic epilepsy syndromes. Pediatric epilepsy patients can be tested using NGS epilepsy panels to diagnose them, thereby influencing treatment choices (Mei et al., 2017). The primary objective of this study was to evaluate the impact of genetic testing on clinical decision making in pediatric epilepsy patients referred to a tertiary epilepsy center, regarding both further planning/omitting of diagnostic procedures and therapeutic options.

Methods: We completed a single-center retrospective cohort study of 91 patients (43 male) aged 19 years or less undergoing NGS with epilepsy panels differing in size ranging from 5 to 434 genes from October 2013 to September 2017.

Results: During a mean time of 3.6 years between symptom onset and genetic testing subjects most frequently showed epileptic encephalopathy (40%), focal epilepsy (33%) and generalized epilepsy (18%). In 16 patients (18%) of the study population “pathogenic” or “likely pathogenic” results according to ACMG criteria were found. In 10 of the 16 patients (63%) clinical management regarding both further diagnostic evaluation and subsequent therapy was changed once the genetic diagnosis was established. Change in therapy comprised both the introduction of new AEDs and tapering/omitting of sodium channel blockers (SOBs) in patients with SCN1A related epilepsy. In eight out of 16 patients (50%) further diagnostic procedures could be prevented due to their genetic test result (most likely a brain MRI-follow-up in anesthesia or long term EEG video monitoring for presurgical evaluation).

Discussion: Our findings suggest that in some cases diagnostic procedures might have been omitted when genetic testing would have been performed at an earlier stage. Patient and parents must readably be consulted prior to NGS testing that the most likely result of a comprehensive test (more than 100 genes) will be the identification of a variant of unknown significance (VUS). In our study the observation of a VUS was made in 38 out of 91 patients (41%), being the most frequent NGS test result. Additional testing of the parents and future discoveries might increase the chance of a molecular diagnosis. Limitations of our study are that it is a retrospective and descriptive study in a relatively small sample size, therefore a certain bias of putative management changes can not be excluded.

Conclusion: NGS epilepsy panels contribute to the diagnosis of pediatric epilepsy patients and may change their clinical management with respect to both preventing unnecessary and potentially harmful diagnostic procedures and management. Thus, the present data support the early implementation in order to adopt clinical management in selected cases and prevent further invasive investigations.

Reference

1. Mei D, Parrini E, Marini C, Guerrini R. The impact of next-generation sequencing on the diagnosis and treatment of epilepsy in paediatric patients. Mol Diagn Ther 2017;21(4):357–373

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No conflict of interest has been declared by the author(s).