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

Abstract

In 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.

The contribution of X-linked coding variation to severe developmental disorders

“…We found that about three-quarters of this burden was in known DD genes. These proportions are similar to findings in other exome-sequencing studies of similar cohorts [39][40][41] . For example, in one of the largest comparable studies, 34/938 (3.6% [2.5%-5.0%]) male probands and 29/728 (4.0% [2.7%-5.7%]) female probands with neurological disorders had a diagnostic X-linked variant 41 , versus 3.8% and 5.4% respectively in DDD (inferred from burden analysis in known DD-associated genes).…”

Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development

“…To investigate the impact of Wwox deficiency on human brain developmental processes, we performed brain histopathological analyses of the 21th week aborted fetus (II.3) with WOREE syndrome and identified abnormal architecture of the developing cerebral cortex. Development of the cerebral cortex is a very dynamic and highly organized process, involving a series of complex morphogenetic events, which can be impaired in different neurodevelopmental disorders (Fernández-Marmiesse et al, 2019;Seto and Eiraku, 2019;Magdalon et al, 2020). Following division of progenitor cells in the ventricular zone, neurons undergo several physiological changes and migrate outward toward the cortical plate, where they differentiate and integrate into functional neural circuits (Romero et al, 2018).…”

Familial SYN1 Pathogenic Mutations Related Neurodevelopmental Disorders in Asian Pediatric Patients

“…Since Garcia CC et al rstly connected SYN1 mutation with neurodevelopmental disorder in 2004, 16 causative variants including ten missense mutations, ve nonsense mutations, and one splicing site mutation in the gene have been identi ed (containing this study) (Fig. 2) [1,2,[7][8][9][10][11][12][13][14][15][16]. These variants are clustered in B linker domain (A51G, S79W), actin-binding and synaptic-vesicle binding C-domain (W126X, W126R, c.527+1G>A, S212I, G240R, V266M, W356X, T359K, R420G) and proline-rich D-domain (R422X, Q482X, A550T, Q555X, T567A) of the encoded protein as indicated (Fig.…”

“…To better understand the clinical characteristics of SYN1-related disorder, we conducted a literature review of all reported pedigrees from the Pubmed and Embase on English articles. Clinical information of 7 pedigrees with the disorder from 7 studies was collected in the report (Table 1) [2,[9][10][11][12][13][14], and other cases were excluded for lack of detail descriptions [1,7,8,15,16]. Overall, we noticed that females are less susceptible than males due to X-chromosome random inactivation (XCI), however, few female carriers presented with mild intellectual disability and febrile seizures [8,14].…”