Importance of targeted next-generation sequencing in pediatric patients with developmental epileptic encephalopathy

Abstract

SUMMARY OBJECTIVE: Childhood epilepsy is a common neurological disorder with a prevalence of 300–600 cases per 100,000 people. It is associated with refractory epilepsies, global developmental delay, and epileptic encephalopathies, causing epileptic syndromes characterized by cognitive and behavioral disorders. METHODS: In this retrospective cohort study, patients with refractory epilepsy and global developmental delay, defined as epileptic encephalopathy, who applied to the Aydın 7Maternity and Children’s Hospital Genetic Diagnosis Center and were followed in the pediatric neurology clinic of our hospital, between July 2018 and July 2021, were included. RESULTS: Targeted next-generation sequencing molecular genetics results were reviewed, and 3 ALDH7A1, 1 AARS, 3 CACNA1A, 1 CTNNB1, 1 DCX, 2 DBH, 2 DOCK7, 1 FOLR1, 2 GABRB3, 2 GCH1, 1 VGRIN2B, 1 GUF1, 3 KCNQ2, 2 KCNT1, 1 NECAP1, 1 PCDH19, 1 PNPO, 1 SCN8A, 1 SCN9A, 4 SCN1A, 2 SLC25A22, 1 SLC2A1, 2 SPTAN1, 2 SZT2, 4 TBC1D24, 2 TH, and 1 PCDH19 (X chromosome) mutations were detected in three of the patients using the next-generation sequencing method. CONCLUSION: Although the development of gene panels aids in diagnosis, there are still unidentified disorders in this illness category, which is highly variable in genotype and phenotype. Understanding the genetic etiology is vital for genetic counseling and, maybe, the future development of remedies for the etiology.

Panel testing may not be sufficient to reveal the etiology of suspected genetic epilepsy

“…The most commonly mutated genes in this cohort were the SCN1A and TBC1D24 genes, followed by the CACNA1A and KCNQ2 genes 1 . A pathogenic variant was detected only in three patients ( ALDH7A1, KCNQ2 , and SCN1A ) 1 . It has been concluded that gene panels support the diagnosis of refractory epilepsy, whereas the undiagnosed conditions remain 1 .…”

“…A pathogenic variant was detected only in three patients ( ALDH7A1, KCNQ2 , and SCN1A ) 1 . It has been concluded that gene panels support the diagnosis of refractory epilepsy, whereas the undiagnosed conditions remain 1 . The study is impressive, but some points require discussion.…”

“…The major limitation of the study is that the pathogenicity of the detected variants was not confirmed by functional or biochemical analysis but only by in silico testing 1 . No population data, computational data, functional data, or segregation data were described.…”

“…We read with interest the article by Baris et al, which is a retrospective, cross-sectional cohort study on 198 pediatric patients with refractory epilepsy and global developmental delay enrolled between July 2018 and July 2021 based on the presence of a pathogenic variant, as assessed by a panel for mutations in genes associated with genetic epilepsy 1 . The most commonly mutated genes in this cohort were the SCN1A and TBC1D24 genes, followed by the CACNA1A and KCNQ2 genes 1 . A pathogenic variant was detected only in three patients ( ALDH7A1, KCNQ2 , and SCN1A ) 1 .…”

“…The second limitation is that a panel testing was performed 1 , which has the disadvantage that new mutated genes not included in the panel may be missed. Panel studies allow only confirm what has been reported previously, while whole exome sequencing (WES) or whole genome sequencing (WGS) allows the detection of a broader spectrum of disease-causing variants.…”