A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations

Abstract

A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.

A unique de novo gain-of-function variant in CAMK4 associated with intellectual disability and hyperkinetic movement disorder

“…Together, these findings buttress the hypothesis that CAMK4 c.981+1G>A (p.Lys303Serfs*28) is a dominant disease-relevant mutation that causes our proband's phenotype via a pathophysiological mechanism other than heterozygous loss of protein activity. This interpretation is in accordance with recent studies demonstrating that rare carboxyl-terminal PTVs can be found in dominant disease genes and that these mutations do not act through haploinsufficiency (Simpson et al 2011; Hood et al 2012; White et al 2015; Jansen et al 2017; Palmer et al 2017). We attempted to identify additional putative CAMK4 gain-of-function variants (PTVs predicted to mediate selective loss of the autoregulatory domain of CaMKIV) in 100 internal exomes from Czech dystonia probands (Helmholtz Center Munich) and in more than 13,000 neurodevelopmental disease trio exomes available through denovo-db (Turner et al 2017).…”

Social and non-social autism symptoms and trait domains are genetically dissociable

“…In addition, gene-based analysis identified four significant genes SDCCAG8 , ZSWIM6 , ZNF574 , and FUT8 (Supplementary Data 2). Of these, mutations in ZSWIM6 cause a neurodevelopmental disorder with, in some cases, co-morbid autism and unusually repetitive movements and behaviour 56 . As supporting analyses, we investigated the direction of effect for all independent SNPs with P < 1 × 10 −6 in the non-stratified SQ-R GWAS in GWAS of autism 57 , educational attainment 58 , and cognitive aptitude 59 .…”

Severe neurocognitive and growth disorders due to variation in THOC2 , an essential component of nuclear mRNA export machinery

“…Dramatic improvements in high‐throughput DNA sequencing technologies and analyses software has led to identification of new ID genes and additional variants in the known ID genes (Dickinson et al., ; Vissers, et al., ). A systematic review of clinical data suggests that ID affected individuals frequently have comorbid neurological, psychiatric, and behavioral disorders (Oeseburg, Dijkstra, Groothoff, Reijneveld, & Jansen, ; Vissers et al., ), and disease variants in different parts of a gene can lead to a broad range of complex neurocognitive disorders (Palmer et al., ; Zhu, Need, Petrovski, & Goldstein, ). This complexity contributes to heterogeneity in clinical symptoms and indistinct boundaries between syndromic and nonsyndromic forms of neurodevelopmental disorder (NDD).…”