Mutations inHECW2are associated with intellectual disability and epilepsy

Abstract

BackgroundDe novo mutations are a frequent cause of disorders related to brain development. We report the results of screening patients diagnosed with both epilepsy and intellectual disability (ID) using exome sequencing to identify known and new causative de novo mutations relevant to these conditions.MethodsExome sequencing was performed on 39 patient–parent trios to identify de novo mutations. Clinical significance of de novo mutations in genes was determined using the American College of Medical Genetics and Genomics standard guidelines for interpretation of coding variants. Variants in genes of unknown clinical significance were further analysed in the context of previous trio sequencing efforts in neurodevelopmental disorders.ResultsIn 39 patient–parent trios we identified 29 de novo mutations in coding sequence. Analysis of de novo and inherited variants yielded a molecular diagnosis in 11 families (28.2%). In combination with previously published exome sequencing results in neurodevelopmental disorders, our analysis implicates HECW2 as a novel candidate gene in ID and epilepsy.ConclusionsOur results support the use of exome sequencing as a diagnostic approach for ID and epilepsy, and confirm previous results regarding the importance of de novo mutations in this patient group. The results also highlight the utility of network analysis and comparison to previous large-scale studies as strategies to prioritise candidate genes for further studies. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy and highlights HECW2 as a new candidate gene for neurodevelopmental disorders.

Loss of the neurodevelopmental gene Zswim6 alters striatal morphology and motor regulation

“…Curiously, Zswim6 has been shown to interact with the E3 ubiquitin ligase HECW2 29 . Mutations in HECW2 were recently identified in patients with intellectual disability and epilepsy, some of whom also display abnormal, repetitive motor behaviors 30,31 . Further studies are necessary to understand whether, and if so how, Zswim6 participates in these diverse cellular processes.…”

De novo KCNA1 variants in the PVP motif cause infantile epileptic encephalopathy and cognitive impairment similar to recurrent KCNA2 variants

“…Brain MRIs at 6 months of age were normal, though at 2 years Twin B had high signal intensities in the globus pallidus and slightly delayed myelination. A de novo KCNA1 (NM_000217.2) (c.1207C > T) variant leading to the substitution (p.Pro403Ser) was identified in the twins during a large‐scale sequencing study of individuals with intellectual disability and epilepsy (Table and Figure ) (Halvardson et al, ). In silico tools predict this variant to be damaging, and it is not present in the >138,000 exome/genome sequences included in the gnomAD database.…”

Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes

“…In this cohort, we failed to identify genes for which clustering of de novo missense mutations reached statistical significance (Table S4). However, application of our method to the dataset of 4,061 DNMs, containing 583 genes with more than one de novo missense mutation, revealed 15 genes with significant clustering 7,8,[23][24][25] (Table 1, Figure 1, Figures S1-S15). In these genes, a total of 107 de novo missense mutations contributed to mutation clustering, ranging from three to 20 mutations per gene with an average distance ranging from 0 to 354 bp.…”