Clinical next generation sequencing in developmental and epileptic encephalopathies: Diagnostic relevance of data re-analysis and variants re-interpretation

• Published in: European journal of medical genetics Vol. 64; no. 12; p. 104363
• Main Authors: Salinas, Valeria, Martínez, Nerina, Maturo, Josefina Pérez, Rodriguez-Quiroga, Sergio A., Zavala, Lucia, Medina, Nancy, Amartino, Hernán, Sfaello, Ignacio, Agosta, Guillermo, Serafín, Eva Maria, Morón, Dolores González, Kauffman, Marcelo A., Vega, Patricia
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Masson SAS 01.12.2021
• Subjects: Adolescent; Brain Diseases - genetics; Child; Child, Preschool; Epilepsy - genetics; Female; Genetic Association Studies - methods; Genetic Predisposition to Disease - genetics; Genetic Testing - methods; Genetic Variation - genetics; Genotype; High-Throughput Nucleotide Sequencing - methods; Humans; Male; Pediatric epilepsy; Phenotype; Re-interpretation; Recessive epilepsy; Targeted gene panel sequencing; Variants of uncertain significance; Whole exome sequencing; Whole Exome Sequencing - methods; Young Adult; Pediatric epilepsy; Variants of uncertain significance; Targeted gene panel sequencing; Whole exome sequencing; Re-interpretation; Recessive epilepsy
• ISSN: 1769-7212; 1878-0849
• DOI: 10.1016/j.ejmg.2021.104363

Developmental and epileptic encephalopathies (DEE) are complex pediatric epilepsies, in which heterogeneous pathogenic factors play an important role. Next-generation-sequencing based tools have shown excellent effectiveness. The constant increase in the number of new genotype-phenotype associations suggests the periodic need for re-interpretation and re-analysis of genetic studies without positive results. In this study, we report the diagnostic utility of targeted gene panel sequencing and whole exome sequencing in 55 Argentine subjects with DEE, focusing on the utility of re-interpretation and re-analysis of undetermined and negative genetic diagnoses. The new information in biomedical literature and databases was used for the re-interpretation. For re-analysis, sequencing data processing was repeated using updated bioinformatics tools. Initially, pathogenic variants were detected in 21 subjects (38%). After an average time of 29 months, 25% of the subjects without a genetic diagnosis were re-categorized as diagnosed. Finally, the overall diagnostic yield increased to 53% (29 subjects). In consequence of the re-interpretation and re-analysis, we identified novel variants in the genes: CHD2, COL4A1, FOXG1, GABRA1, GRIN2B, HNRNPU, KCNQ2, MECP2, PCDH19, SCN1A, SCN2A, SCN8A, SLC6A1, STXBP1 and WWOX. Our results expand the diagnostic yield of this subgroup of infantile and childhood seizures and demonstrate the importance of re-evaluation of genetic tests in subjects without an identified causative etiology. •The re-interpretation and re-analysis of genetic tests in subjects with pediatric epilepsies is crucial.•NGS was useful to obtain the genetic diagnosis in 53% of patients with Developmental and epileptic encephalopathy.•More than 50% of the variants were novel according to biomedical literature.•52% of the identified variants are linked to channelopathies.