Abstract
Epileptic encephalopathies (EEs) and developmental and epileptic encephalopathies (DEEs) are a group of severe early-onset neurodevelopmental disorders (NDDs). In recent years, next-generation equencing (NGS) technologies enabled the discovery of numerous genes involved in these conditions. However, more than 50% of patients remained undiagnosed. A major obstacle lies in the high degree of genetic heterogeneity and the wide phenotypic variability that has characterized these disorders. Interpreting a large amount of NGS data is also a crucial challenge. This study describes a dynamic diagnostic procedure used to investigate 17 patients with DEE or EE with previous negative or inconclusive genetic testing by whole-exome sequencing (WES), leading to a definite diagnosis in about 59% of participants. Biallelic mutations caused most of the diagnosed cases (50%), and a pathogenic somatic mutation resulted in 10% of the subjects. The high diagnostic yield reached highlights the relevance of the scientific approach, the importance of the reverse phenotyping strategy, and the involvement of a dedicated multidisciplinary team. The study emphasizes the role of recessive and somatic variants, new genetic mechanisms, and the complexity of genotype–phenotype associations. In older patients, WES results could end invasive diagnostic procedures and allow a more accurate transition. Finally, an early pursued diagnosis is essential for comprehensive care of patients, precision approach, knowledge of prognosis, patient and family planning, and quality of life.
Highlights
The enormous flow of information resulting from the application of next-generation sequencing (NGS) techniques and the continued identification of new genes are changing the approach to early-onset epilepsies; the greatest success in discovering the epilepsy genes came from the study of epileptic encephalopathies (EEs) [1]
Our study identified molecular diagnosis in around 59% of participants, a yield higher than a range of 30% to 50% of developmental and epileptic encephalopathies (DEEs) attributed to a pathogenic variant [55,56]
The present study demonstrates once more how rare and severe EEs, DEES, and neurodevelopmental disorders (NDDs) have become more susceptible to diagnosis, with relevant significance for substantial approach and treatment options even in undiagnosed older and adult patients [84]
Summary
The enormous flow of information resulting from the application of next-generation sequencing (NGS) techniques and the continued identification of new genes are changing the approach to early-onset epilepsies; the greatest success in discovering the epilepsy genes came from the study of epileptic encephalopathies (EEs) [1]. The increased knowledge of the etiology and underlying pathophysiological processes provided by genetic research have prompted clinicians to adopt different perspectives and nosological frameworks for accurate phenotypic characterizations and phenotype–genotype correlations [4,5] In this regard, the term developmental and epileptic encephalopathies (DEEs) has been coined to define genetic wide electroclinical syndromes characterized by epilepsy, developmental delay or regression or intellectual disability, an abnormal EEG, and other possible neurological or systemic manifestations. Increasing evidence suggests that a large percentage of NDD cases may be genetically complex and may occur through models involving mosaicisms, epigenetic mechanisms, and digenic/polygenic inheritance [24] This complexity can confuse clinicians who rely on their diagnostic suspicion of the patient’s phenotypic characteristics and the available literature. There is a rush to pursue the benefits of molecular diagnosis in older patients and in adults [27–29]
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