Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability

PLoS One. 2017 Apr 17;12(4):e0175962. doi: 10.1371/journal.pone.0175962. eCollection 2017.


By searching a clinical database of over 60,000 individuals referred for array-based CNV analyses and online resources, we identified four males from three families with intellectual disability, developmental delay, hypotonia, joint hypermobility and relative macrocephaly who carried small, overlapping deletions of Xp11.22. The maximum region of overlap between their deletions spanned ~430 kb and included two pseudogenes, CENPVL1 and CENPVL2, whose functions are not known, and two protein coding genes-the G1 to S phase transition 2 gene (GSPT2) and the MAGE family member D1 gene (MAGED1). Deletions of this ~430 kb region have not been previously implicated in human disease. Duplications of GSPT2 have been documented in individuals with intellectual disability, but the phenotypic consequences of a loss of GSPT2 function have not been elucidated in humans or mouse models. Changes in MAGED1 have not been associated with intellectual disability in humans, but loss of MAGED1 function is associated with neurocognitive and neurobehavioral phenotypes in mice. In all cases, the Xp11.22 deletion was inherited from an unaffected mother. Studies performed on DNA from one of these mothers did not show evidence of skewed X-inactivation. These results suggest that deletions of an ~430 kb region on chromosome Xp11.22 that encompass CENPVL1, CENPVL2, GSPT2 and MAGED1 cause a distinct X-linked syndrome characterized by intellectual disability, developmental delay, hypotonia, joint hypermobility and relative macrocephaly. Loss of GSPT2 and/or MAGED1 function may contribute to the intellectual disability and developmental delay seen in males with these deletions.

MeSH terms

  • Antigens, Neoplasm / genetics*
  • Child
  • Child, Preschool
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosome Duplication / genetics
  • Chromosomes, Human, X / genetics*
  • Comparative Genomic Hybridization / methods
  • Developmental Disabilities / genetics
  • Female
  • Genes, X-Linked / genetics*
  • Humans
  • Intellectual Disability / genetics*
  • Male
  • Neoplasm Proteins / genetics*
  • Pedigree
  • Peptide Termination Factors / genetics*
  • Phenotype
  • Sequence Deletion / genetics*
  • X Chromosome Inactivation / genetics


  • Antigens, Neoplasm
  • CENPV protein, human
  • Chromosomal Proteins, Non-Histone
  • MAGED1 protein, human
  • Neoplasm Proteins
  • Peptide Termination Factors
  • peptide-chain-release factor 3

Grants and funding

This work was supported, in part, by the National Institutes of Health/ National Institute of General Medical Sciences Initiative for Maximizing Student Development [R25 GM056929-16]. Baylor Genetics provided support in the form of salaries for authors FX and SWC. The specific roles of these authors are articulated in the 'author contributions' section. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from genetic analyses offered through Baylor Genetics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.