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

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 Genetic Diagnosis of Ultrarare DEEs: An Ongoing Challenge

“…Our study identified molecular diagnosis in around 59% of participants, a yield higher than a range of 30% to 50% of DEEs attributed to a pathogenic variant [55,56]. As recently suggested, these results confirmed that the probability of reaching a correct diagnosis was enhanced by the methodological approach, particularly by in-depth phenotyping and the reanalysis of previous negative or uncertain sequencing data [18].…”

“…All selected variants were confirmed, and segregation analysis was performed with Sanger sequencing. A reverse phenotyping strategy was used to refine the phenotype based on the interpretation of genetic data [ 18 ].…”

“…The currently achievable diagnostic yield of WES in DEE S is 31–53% [ 14 , 15 , 16 , 17 ]. The difficulty deriving from the management of large amounts of WES data and from the interpretation of the pathogenic role of variants is one of the causes of undiagnosed patients [ 18 , 19 , 20 , 21 ]. The iterative and collaborative process between research and diagnostic laboratories, combining ongoing analysis with clinically oriented interpretation, can lead to a genetic diagnosis for a part of these subjects, including patients for whom clinical genetic tests had failed to produce definitive results [ 22 , 23 ].…”

Thalamocortical circuits in generalized epilepsy: Pathophysiologic mechanisms and therapeutic targets

“…The true prevalence of DEEs is not well established, although it has been estimated that the overall annual incidence of monogenic epilepsies is around 1 per 2100 live births ( Symonds et al, 2019 ; Aledo-Serrano et al, 2021 ).…”

Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies

“…If this primary diagnostic strategy is not conclusive ( 61 ), a reinterpretation of the pathogenicity of the detected variants (especially those variants of uncertain significance -VUS-) ( 62 ) and a reappraisal of the obtained results concerning the quality of the sequencing process (see the next section Considerations on Interpreting the Results of Genetic Testing) is warranted.…”