HUWE1 mutations in Juberg-Marsidi and Brooks syndromes: the results of an X-chromosome exome sequencing study

Abstract

BackgroundX linked intellectual disability (XLID) syndromes account for a substantial number of males with ID. Much progress has been made in identifying the genetic cause in many of the syndromes described 20–40 years ago. Next generation sequencing (NGS) has contributed to the rapid discovery of XLID genes and identifying novel mutations in known XLID genes for many of these syndromes.Methods2 NGS approaches were employed to identify mutations in X linked genes in families with XLID disorders. 1 involved exome sequencing of genes on the X chromosome using the Agilent SureSelect Human X Chromosome Kit. The second approach was to conduct targeted NGS sequencing of 90 known XLID genes.ResultsWe identified the same mutation, a c.12928 G>C transversion in the HUWE1 gene, which gives rise to a p.G4310R missense mutation in 2 XLID disorders: Juberg-Marsidi syndrome (JMS) and Brooks syndrome. Although the original families with these disorders were considered separate entities, they indeed overlap clinically. A third family was also found to have a novel HUWE1 mutation.ConclusionsAs we identified a HUWE1 mutation in an affected male from the original family reported by Juberg and Marsidi, it is evident the syndrome does not result from a mutation in ATRX as reported in the literature. Additionally, our data indicate that JMS and Brooks syndromes are allelic having the same HUWE1 mutation.

The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development

“…At present, 7 different missense mutations in HUWE1 are associated with intellectual disability, and several mutations affect residues conserved in C. elegans EEL-1 (Friez et al, 2016; Froyen et al, 2008). Two of these mutations are shown in Figure 1A.…”

“…Increased copies of HUWE1 are associated with non-syndromic intellectual disability (Friez et al, 2016 #922; Froyen et al, 2012; Froyen et al, 2008; Madrigal et al, 2007). Missense mutations in HUWE1 occur in multiple families with intellectual disability, including families with Juberg-Marsidi-Brooks syndrome (Friez et al, 2016; Froyen et al, 2008; Isrie et al, 2013). This suggests both increased and decreased HUWE1 function could be associated with intellectual disability, but evidence from an in vivo model system supporting or refuting this possibility remains absent.…”

A HS6ST2 gene variant associated with X‐linked intellectual disability and severe myopia in two male twins

“…18 To date, there is no evidence of HS6ST2 involvement in Mendelian diseases. [19][20][21][22] ID, speech delay, and severe myopia in a context of mild dysmorphia were the specific key features supporting the similarity. Moreover, the three BWB patients described by Morava et al 21 presented with increased blood lactate values in infancy, similar to the affected twins.…”

“…Despite this, WES analysis excluded the presence of pathogenic variants of the HUWE1 gene, which was identified by Friez et al as a causal gene for BWB. 22 In addition, there were clinical discrepancies between the affected probands and the BWB patients described in the literature. The boys described by Brooks et al 19 presented with spastic diplegia, optic and cerebellar atrophy, and entropion, which were not noted in our cases; the majority of patients reported by Morava 20,21 exhibited regression, seizures, and corpus callosum hypogenesis that were not present in the patients described in the current study.…”

“…The boys described by Brooks et al 19 presented with spastic diplegia, optic and cerebellar atrophy, and entropion, which were not noted in our cases; the majority of patients reported by Morava 20,21 exhibited regression, seizures, and corpus callosum hypogenesis that were not present in the patients described in the current study. Given that BWB syndrome is an extremely rare disorder and exhibits a high degree of clinical heterogeneity, [19][20][21][22] it is possible that BWB could be genetically heterogeneous and that the phenotype of HSPGs reside on the plasma membranes of all animal cells studied to date and are major components of the extracellular matrix. Studies of model organisms have demonstrated their importance in development and normal physiology.…”