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Aledo-Serrano et al. J Transl Genet Genom 2021;5:443-55 Journal of Translational
DOI: 10.20517/jtgg.2021.40
Genetics and Genomics

Review Open Access

Developmental and epileptic encephalopathies after
negative or inconclusive genetic testing: what is

next?

2
1,3
1
1,4
Angel Aledo-Serrano , Rocío Sánchez-Alcudia , Rafael Toledano , Irene García-Morales , Álvaro Beltrán-
5
1
Corbellini , Isabel del Pino , Antonio Gil-Nagel 1
1
Epilepsy Program, Department of Neurology, Ruber Internacional Hospital, Madrid 28034, Spain.
2
Department of Clinical Genetics, Blueprint Genetics, Espoo 02150, Finland.
3
Epilepsy Unit, Department of Neurology, Ramon y Cajal University Hospital, Madrid 28034, Spain.
4
Epilepsy Unit, Department of Neurology, Clinico San Carlos University Hospital, Madrid 28040, Spain.
5
Principe Felipe Research Center (Centro de Investigación Principe Felipe, CIPF), Valencia 46012, Spain.
Correspondence to: Angel Aledo-Serrano, MD, PhD, Epilepsy Program, Department of Neurology, Ruber Internacional Hospital,
c/ La Maso, 38, Madrid 28034, Spain. E-mail: aaledo@neurologiaclinica.es
How to cite this article: Aledo-Serrano A, Sánchez-Alcudia R, Toledano R, García-Morales I, Beltrán-Corbellini Á, del Pino I, Gil-
Nagel A. Developmental and epileptic encephalopathies after negative or inconclusive genetic testing: what is next? J Transl
Genet Genom 2021;5:443-55. https://dx.doi.org/10.20517/jtgg.2021.40
Received: 20 Aug 2021 First Decision: 18 Sep 2021 Revised: 18 Sep 2021 Accepted: 9 Oct 2021 Published: 5 Dec 2021
Academic Editor: Jobin Varkey Copy Editor: Yue-Yue Zhang Production Editor: Yue-Yue Zhang

Abstract
The redefinition of classical electroclinical syndromes and the emergence of neurogenetics has led to a revolution
in the field of developmental and epileptic encephalopathies (DEEs). In this context, advances in genetic techniques
are leading to the final diagnosis of a large proportion of patients with DEE. However, up to 50% of patients with
DEE remain undiagnosed. For patients with uncertain genetic etiology, there is a pressing need for the
implementation of new targeted treatments and precision medicine. In some undiagnosed patients, genetic
reanalysis with further in-depth or reverse phenotyping are valuable diagnostic tools to clarify new variants of
uncertain significance. In other cases, the implementation of new bioinformatic algorithms is required for the
update and reassessment of previously generated genetic data. Moreover, many other clinical tools have been
developed for the management of patients of DEEs after a negative or inconclusive genetic testing. In this review,
we highlight advances and limitations of new diagnostic strategies used in DEE patients without a known genetic
etiology. Finally, we provide a wide perspective on aspects that will need further research, especially in non-
Mendelian inheritance DEEs, such as those related to somatic mosaicism of the central nervous system or
epigenetic and oligogenic mechanisms.

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.

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