Phenotypic and Genotypic Spectrum of Early-Onset Developmental and Epileptic Encephalopathies—Data from a Romanian Cohort

Abstract

Early-onset developmental epileptic encephalopathy (DEE) refers to an age-specific, diverse group of epilepsy syndromes with electroclinical anomalies that are associated with severe cognitive, behavioral, and developmental impairments. Genetic DEEs have heterogeneous etiologies. This study includes 36 Romanian patients referred to the Regional Centre for Medical Genetics Dolj for genetic testing between 2017 and 2020. The patients had been admitted to and clinically evaluated at Doctor Victor Gomoiu Children’s Hospital and Prof. Dr. Alexandru Obregia Psychiatry Hospital in Bucharest. Panel testing was performed using the Illumina® TruSight™ One “clinical exome” (4811 genes), and the analysis focused on the known genes reported in DEEs and clinical concordance. The overall diagnostic rate was 25% (9/36 cases). Seven cases were diagnosed with Dravet syndrome (likely pathogenic/pathogenic variants in SCN1A) and two with Genetic Epilepsy with Febrile Seizures Plus (SCN1B). For the diagnosed patients, seizure onset was <1 year, and the seizure type was generalized tonic-clonic. Four additional plausible variants of unknown significance in SCN2A, SCN9A, and SLC2A1 correlated with the reported phenotype. Overall, we are reporting seven novel variants. Comprehensive clinical phenotyping is crucial for variant interpretation. Genetic assessment of patients with severe early-onset DEE can be a powerful diagnostic tool for clinicians, with implications for the management and counseling of the patients and their families.

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children

“…We report a significant proportion of variants (29%), both reported and novel, classified as VUSs in our study where the evidence is not as strong to classify these variants as pathogenic or benign. This was observed in previous studies 22,24 including individuals from underrepresented populations similar to our study 21,23 and represents a diagnostic challenge as these are not considered clinically diagnostic and require further clinical assessment, familial/segregation studies, RNA/splicing studies (for non-coding or splicing variants) or functional studies for further pathogenicity/ benignity reclassification, 22 which was not be possible in some families due to families declining familial/segregation studies, or unavailability of RNA/functional studies.…”

“…The estimated diagnostic yield of ES in DEEs in our study was 30%, which is similar to the previous reports for genome sequencing in DEEs (25%–45%) in recent studies 18–22 . There was marked genetic heterogeneity observed in our cohort, with variants identified in 33 genes and none of the genes being predominant in the cohort.…”

“…The estimated diagnostic yield of ES in DEEs in our study was 30%, which is similar to the previous reports for genome sequencing in DEEs (25%-45%) in recent studies. [18][19][20][21][22] There was marked genetic heterogeneity observed in our cohort, with variants identified in 33 genes and none of the genes being predominant in the cohort. This was similar to previous reports in various populations [20][21][22][23] and highlights the diagnostic challenges in DEEs and the importance of exome/genome sequencing rather than targeted gene testing in genetic diagnosis in DEEs.…”

“…[18][19][20][21][22] There was marked genetic heterogeneity observed in our cohort, with variants identified in 33 genes and none of the genes being predominant in the cohort. This was similar to previous reports in various populations [20][21][22][23] and highlights the diagnostic challenges in DEEs and the importance of exome/genome sequencing rather than targeted gene testing in genetic diagnosis in DEEs. We report a significant proportion of variants (29%), both reported and novel, classified as VUSs in our study where the evidence is not as strong to classify these variants as pathogenic or benign.…”

Comprehensive scoping review of fenfluramine's role in managing generalized tonic–clonic seizures in developmental and epileptic encephalopathies

“…A smaller study of 36 patients with DEEs also reported that 64% of patients were experiencing GTCS. 48 One of the main goals of DEE treatment is to alleviate seizure burden by targeting the most problematic seizure type. 10 Although total cessation of seizures is not likely to be attainable for these patients, a reduction, especially of the most severe seizures, could mitigate neurodevelopmental delay, improve QOL, minimize polypharmacy, and reduce injury and premature death, namely, SUDEP.…”