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

BMJ Open. 2016 Apr 29;6(4):e009537. doi: 10.1136/bmjopen-2015-009537.


Background: X 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.

Methods: 2 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.

Results: We 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.

Conclusions: As 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Chromosomes, Human, X / genetics*
  • Deafness / genetics*
  • Exome
  • Facies
  • Genetic Diseases, X-Linked
  • Growth Disorders / genetics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hypogonadism / genetics*
  • Intellectual Disability
  • Male
  • Megalencephaly
  • Mental Retardation, X-Linked / genetics*
  • Middle Aged
  • Muscle Spasticity / genetics*
  • Mutation
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases / genetics*
  • Young Adult


  • Tumor Suppressor Proteins
  • HUWE1 protein, human
  • Ubiquitin-Protein Ligases

Supplementary concepts

  • Mental Retardation, X-Linked, Syndromic, Turner Type
  • Mental retardation-hypotonic facies syndrome, x-linked, 1