Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients

Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients

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In order to characterize the genetic architecture of epilepsy in a camo party invitations pediatric population from the Iberian Peninsula (including the Canary Islands), we conducted targeted exome sequencing of 246 patients with infantile-onset seizures with or without neurodevelopmental delay.We detected 107 variants in 48 different genes, which were implicated in neuronal excitability, neurodevelopment, synaptic transmission, and metabolic pathways.In 104 cases (42%) we detected variant(s) that we classified as pathogenic or likely pathogenic.Of the 48 mutated genes, 32 were dominant, 8 recessive and 8 X-linked.

Of the patients for whom family studies could be performed and in whom pathogenic variants were identified in dominant or X-linked genes, 82% carried de novo mutations.The involvement of small copy number variations (CNVs) is 9%.The use of progressively updated custom panels with high mean vertical coverage enabled establishment of a definitive diagnosis in a large proportion of cases (42%) and detection of CNVs (even duplications) with high fidelity.In 10.

5% of patients we detected associations that are pending confirmation via functional and/or familial studies.Our findings had important consequences for the clinical management of the probands, since a large proportion of the cohort had been clinically misdiagnosed, and their families were subsequently able to avail of genetic counseling.In some cases, a more appropriate treatment was selected for the patient in question, or an inappropriate treatment bondi 2 seater sofa discontinued.Our findings suggest the existence of modifier genes that may explain the incomplete penetrance of some epilepsy-related genes.

We discuss possible reasons for non-diagnosis and future research directions.Further studies will be required to uncover the roles of structural variants, epimutations, and oligogenic inheritance in epilepsy, thereby providing a more complete molecular picture of this disease.In summary, given the broad phenotypic spectrum of most epilepsy-related genes, efficient genomic tools like the targeted exome sequencing panel described here are essential for early diagnosis and treatment, and should be implemented as first-tier diagnostic tools for children with epilepsy without a clear etiologic basis.