The Neuropediatrics service and the Genetics Unit of the Marques de Valdecilla University Hospital have published in the Frontiers Neuroscience the study “Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients”, a collaborative work in which geneticists and neuropediatras from all over Spain and Portugal have participated.
The objective of this work has been to characterize the genetic architecture of epilepsy in the pediatric population of the Iberian and Canary Islands, carrying out a targeted sequencing of 246 patients with epileptic seizures of childhood onset with or without delay in neurological development. 107 variants were detected in 48 different genes, involved in neuronal excitability, neurological development, synaptic transmission and metabolic pathways. In 42% of the cases, variants that were classified as pathogenic or probably pathogenic were detected. Of the 48 mutated genes, 32 were dominant, 8 were recessive and 8 linked to the X chromosome. Of the patients for whom family studies could be performed, it was shown that the mutations were de novo (not inherited) in 82% of the cases. Variations in the number of copies (large losses or gains of DNA) in the global mutational load was 9%.
For this study, customized panels progressively updated with high vertical mean coverage were used, which allowed the establishment of a definitive diagnosis in a large proportion of cases (42%) and the detection of CNV (even duplication) with high fidelity. In 10.5% of the patients associations were detected that are pending confirmation through functional and / or family studies.
The results obtained had important consequences for the clinical management of the patients, since a significant proportion of them had been misdiagnosed, and their families were finally able to resort to genetic counseling. In some cases, a more appropriate treatment was selected for the patient in question, or an inappropriate treatment was discontinued.
Likewise, the results of this study also suggest the existence of modifying genes that may explain the incomplete penetrance of some epilepsy-related genes. Further studies will be required to discover the role of structural variants, epimutations (epigenetics) and oligogenic inheritance in epilepsy, thus providing a more complete molecular picture of this disease.
To conclude, given the broad phenotypic spectrum of most epilepsy-related genes, the use of efficient genomic tools such as that used in this study is essential for early diagnosis and treatment, and therefore should be implemented as tools for first level diagnosis for children with epilepsy without a clear etiological basis.
Thus, the indication of such genomic tools, which cover the broad clinical spectrum, in other pediatric diseases of genetic basis could be extended.
Ref. Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients. Fernández-Marmiesse A, Roca I, Díaz-Flores F, Cantarín V, Pérez-Poyato MS, Fontalba A, Laranjeira F, Quintans S, Moldovan O, Felgueroso B, Rodríguez-Pedreira M, Simón R, Camacho A, Quijada P, Ibanez-Mico S, Domingno MR, Benito C, Calvo R, Pérez-Cejas A, Carrasco ML, Ramos F, Couce ML, Ruiz-Falcó ML, Gutierrez-Solana L, Martínez-Atienza M.
