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.
Highlights
The field of epilepsy genetics has emerged in clinical practice and is rapidly evolving in the last years
The main group of epilepsies where a genetic etiology can be found are the developmental and epileptic encephalopathies (DEEs), defined as wide electroclinical syndromes characterized by epilepsy, developmental delay or regression or intellectual disability, an abnormal EEG, and other possible neurological or systemic manifestations[1]
This recent epidemiological research on genetic epilepsies led to elucidating some of the most common genes associated with DEEs, such as SCN1A, KCNQ2, PCDH19, CDKL5, SCN2A, and SCN8A, among others[3]
Summary
The field of epilepsy genetics has emerged in clinical practice and is rapidly evolving in the last years. The aims of this narrative review are: (1) to understand the limitations in the diagnosis of classical epileptic syndromes and their reframing in light of the most recent advances in genetic epidemiology; (2) to describe the reverse phenotyping strategy and its importance in the clinical practice regarding patients with DEEs; (3) to discuss the management of patients with DEE and negative or inconclusive genetic testing; and (4) to understand the limitations of the current diagnostic approach for these patients and future perspectives.
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