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Page 444 Aledo-Serrano et al. J Transl Genet Genom 2021;5:443-55 https://dx.doi.org/10.20517/jtgg.2021.40

Keywords: Neurodevelopmental disorders, epilepsy, genetic epilepsies, precision medicine, neurogenetics,
diagnostic yield

INTRODUCTION
The field of epilepsy genetics has emerged in clinical practice and is rapidly evolving in the last years. In this
setting, 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 . Next-generation sequencing (NGS) provided a rapid increment
[1]
of gene discoveries in human disorders. The actual prevalence of DEEs is not known yet, although it has
[2]
been estimated that the overall annual incidence of single-gene epilepsies is around 1 per 2100 live births .
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 . Currently, genetic testing is mandatory for determining precision medicine treatments and to
[3]
avoid unnecessary and potentially harmful diagnostic examinations and medications. A genetic diagnosis
might also provide genetic counseling and relevant information on the natural history of a condition, as well
[4]
as the access to new clinical trials or patient support groups .

Multiple lines of evidence showing poor genotype-phenotype correlations in classical electroclinical
syndromes have triggered a redefinition of the traditional concept “epileptic encephalopathy”, as well as a
[5]
revolution in the field of DEEs over the last few years . At the clinical level, these changes promoted the
application of new procedures when studying genetic and phenotypic heterogeneity, e.g., by expanding the
[6]
clinical spectrum related to each gene in a process known as reverse phenotyping . Importantly, since a
large proportion of genes related to epilepsy are also associated with autism or intellectual disability, among
[7]
others , the transition towards the conceptual framework “DEEs” has made it possible to redefine epilepsy
as an additional symptom of neurodevelopmental diseases. Advances in genetic diagnostic techniques have
also led to the confirmed diagnosis of a large proportion of patients with DEEs. However, at least a relevant
[8]
proportion of patients - estimated as 50% - remain undiagnosed . In most cases, patients remain
undiagnosed due to insufficient genetic testing. In others, variants of uncertain significance have been
identified after further in-depth phenotyping. The update of genetic studies and/or the reanalysis of genetic
data with modern computational tools has proved essential as our knowledge of the disease prognosis and
the availably of targeted treatments increases. However, there are still many aspects related to the course of
clinical diagnostic of DEEs that need to evolve to reach precision treatments, especially in non-Mendelian
inherited neurodevelopmental disorders, such as those related to mitochondrial genome, somatic
mosaicism of the central nervous system, or epigenetic alterations [9,10] .

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.

CONCEPTUAL FRAMEWORK SHIFT OF “EPILEPTIC ENCEPHALOPATHY”
Developmental and epileptic encephalopathies are a heterogeneous and complex group of diseases that fall
under the general umbrella of neurodevelopmental disorders, in which epilepsy and cognitive/behavioral
problems are combined in varying proportions, in some cases associated with other comorbidities. There is