000098219 001__ 98219
000098219 005__ 20230914083325.0
000098219 0247_ $$2doi$$a10.3389/fnins.2019.01135
000098219 0248_ $$2sideral$$a121867
000098219 037__ $$aART-2019-121867
000098219 041__ $$aeng
000098219 100__ $$aFernández-Marmiesse, A.
000098219 245__ $$aRare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients
000098219 260__ $$c2019
000098219 5060_ $$aAccess copy available to the general public$$fUnrestricted
000098219 5203_ $$aIn order to characterize the genetic architecture of epilepsy in a 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 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.
000098219 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000098219 590__ $$a3.707$$b2019
000098219 591__ $$aNEUROSCIENCES$$b96 / 270 = 0.356$$c2019$$dQ2$$eT2
000098219 592__ $$a1.554$$b2019
000098219 593__ $$aNeuroscience (miscellaneous)$$c2019$$dQ1
000098219 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000098219 700__ $$aRoca, I.
000098219 700__ $$aDíaz-Flores, F.
000098219 700__ $$aCantarín, V.
000098219 700__ $$aPérez-Poyato, M.S.
000098219 700__ $$aFontalba, A.
000098219 700__ $$aLaranjeira, F.
000098219 700__ $$aQuintans, S.
000098219 700__ $$aMoldovan, O.
000098219 700__ $$aFelgueroso, B.
000098219 700__ $$aRodríguez-Pedreira, M.
000098219 700__ $$aSimón, R.
000098219 700__ $$aCamacho, A.
000098219 700__ $$aQuijada, P.
000098219 700__ $$aIbanez-Mico, S.
000098219 700__ $$aDomingno, M.R.
000098219 700__ $$aBenito, C.
000098219 700__ $$aCalvo, R.
000098219 700__ $$aPérez-Cejas, A.
000098219 700__ $$aCarrasco, M.L.
000098219 700__ $$0(orcid)0000-0002-5732-2209$$aRamos, F.$$uUniversidad de Zaragoza
000098219 700__ $$aCouce, M.L.
000098219 700__ $$aRuiz-Falcó, M.L.
000098219 700__ $$aGutierrez-Solana, L.
000098219 700__ $$aMartínez-Atienza, M.
000098219 7102_ $$11010$$2670$$aUniversidad de Zaragoza$$bDpto. Pediatría Radiol.Med.Fís$$cÁrea Pediatría
000098219 773__ $$g13, 1135 (2019), [17 pp]$$pFront. neurosci.$$tFrontiers in neuroscience$$x1662-4548
000098219 8564_ $$s408385$$uhttps://zaguan.unizar.es/record/98219/files/texto_completo.pdf$$yVersión publicada
000098219 8564_ $$s2812179$$uhttps://zaguan.unizar.es/record/98219/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000098219 909CO $$ooai:zaguan.unizar.es:98219$$particulos$$pdriver
000098219 951__ $$a2023-09-13-11:08:14
000098219 980__ $$aARTICLE