De novo missense variants inHECW2are associated with neurodevelopmental delay and hypotonia

Abstract

Background The causes of intellectual disability (ID) are diverse and de novo mutations are increasingly recognised to account for a significant proportion of ID. Methods and results In this study, we performed whole exome sequencing on a large cohort of patients with ID or neurodevelopmental delay and identified four novel de novo predicted deleterious missense variants in HECW2 in six probands with ID/developmental delay and hypotonia. Other common features include seizures, strabismus, nystagmus, cortical visual impairment and dysmorphic facial features. HECW2 is an ubiquitin ligase that stabilises p73, a crucial mediator of neurodevelopment and neurogenesis. Conclusion This study implicates pathogenic genetic variants in HECW2 as potential causes of neurodevelopmental disorders in humans.

A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors

“…; Berko et al. ; Lammert and Howell ). Notably, a high number of genes identified in developmental delays involve chromatin mediators of gene expression, referred to as epigenetic regulators that likely affect developmental processes in neuron differentiation (Lomvardas and Maniatis ).…”

“…This is somewhat controversial as many share overlapping characteristics, and clarity in definition might be improved as we learn more about genetic variations that serve to identify networks of pathways that play a role in developmental disabilities. Causative mutations and variations in genes contributing to developmental disabilities and pharmacologic effects are much more easily identified by next-generation exome or genome sequencing and targeted genotyping approaches (D'Amours et al 2014;Pisano et al 2015;Berko et al 2016;Lammert and Howell 2016). Notably, a high number of genes identified in developmental delays involve chromatin mediators of gene expression, referred to as epigenetic regulators that likely affect developmental processes in neuron differentiation (Lomvardas and Maniatis 2016).…”

SATB2‐associated syndrome in patients from Japan: Linguistic profiles

“…Germline heterozygous mutations in HECW2 lead to intellectual disabilities with or without epilepsy. So far, only missense mutations, but no truncating mutations, have been reported (Berko et al, ). Based on this lack of reports of truncating mutations, it has been suggested that the implicated HECW2 mutations are gain‐of‐function‐type mutations and not haploinsufficiency‐type mutations.…”

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.…”