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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. eCollection 2017
Christina Grau 1 , Molly Starkovich 1 , Mahshid S Azamian 1 , Fan Xia 2 , Sau Wai Cheung 2 , Patricia Evans 3 , Alex Henderson 4 , Seema R Lalani 1 , Daryl A Scott 5
Christina Grau 1 , Molly Starkovich 1 , Mahshid S Azamian 1 , Fan Xia 2 , Sau Wai Cheung 2 , Patricia Evans 3 , Alex Henderson 4 , Seema R Lalani 1 , Daryl A Scott 5
+ et al

[No authors listed]

Author information
  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
  • 2 Baylor Genetics, Houston, Texas, Unite States of America.
  • 3 Departments of Pediatrics and Neurology, University of Texas Southwestern Medical School, Dallas, Texas, United States of America.
  • 4 The Newcastle upon Tyne Hospitals, Newcastle upon Tyne, England.
  • 5 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States of America.

摘要


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.