Pedigree and array-based CNV analysis for subject 2.

<p>(A) Subject 2 inherited an interstitial Xp11.22 deletion from his asymptomatic mother. (B) Data from the array-based CNV analyses performed on subject 2 and his mother. The approximate locations of the RefSeq genes in this region are shown below. Genes depicted in red are those found in the maximal overlapping region encompassed by the deletions of subjects 1–4. Genes depicted in blue were deleted in a subset of subjects 1–4.</p

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

<div><p>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, <i>CENPVL1</i> and <i>CENPVL2</i>, whose functions are not known, and two protein coding genes—the G1 to S phase transition 2 gene (<i>GSPT2</i>) and the MAGE family member D1 gene (<i>MAGED1</i>). Deletions of this ~430 kb region have not been previously implicated in human disease. Duplications of <i>GSPT2</i> have been documented in individuals with intellectual disability, but the phenotypic consequences of a loss of <i>GSPT2</i> function have not been elucidated in humans or mouse models. Changes in <i>MAGED1</i> 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 <i>CENPVL1</i>, <i>CENPVL2</i>, <i>GSPT2</i> and <i>MAGED1</i> 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.</p></div

Coordinates of Xp11.22 deletions and Xp11.22 genes previously implicated or proposed to be involved in the development of intellectual disability/developmental delay/autism.

<p>Coordinates of Xp11.22 deletions and Xp11.22 genes previously implicated or proposed to be involved in the development of intellectual disability/developmental delay/autism.</p

Photos of subject 1 at various ages.

<p>Subject 1 at (A) 4 days, (B) 6 days, (C) 1 month, (D-E) 1 year, (F) 2 years, and (G) 3 years of age. He does not have dysmorphic features. His congenital muscular torticollis resolved by 2 years of age. He had gross and fine motor delay attributable, at least in part, to his joint hypermobility. He could sit independently by 1 year of age (D) but required bracing to stand (E). At 22 months of age he could walk with the aid of a walker (F) and by 2 years 3 months of age he could walk independently.</p

Pedigree and array-based CNV analysis for subject 1.

<p>(A) Subject 1 inherited an interstitial Xp11.22 deletion from his asymptomatic mother. His unaffected brother does not carry this deletion. Both subject 1 and his unaffected brother carry a maternally-inherited 17q12 deletion. (B) Data from the array-based CNV analyses performed on the subject 1 and his mother. The approximate locations of the RefSeq genes in this region are shown below. Genes depicted in red are those found in the maximal overlapping region encompassed by the deletions of subjects 1–4. Genes depicted in blue were deleted in a subset of subjects 1–4. Genes depicted in gray were not deleted in subjects 1–4.</p

Molecular findings and clinical phenotypes of subjects 1–4.

<p>Molecular findings and clinical phenotypes of subjects 1–4.</p

Schematic representation of the Xp11.22 deletions carried by subjects 1–4.

<p>The minimum (red) and maximum (yellow) deletions of each subject are shown in relation to the positon of Xp11.22 genes. The coordinates shown at the top of the figure are based on hg19. The maximum region of overlap is represented as dashed gray lines. The RefSeq genes located in this critical region—<i>CENPVL1</i>, <i>CENPVL2</i>, <i>GSPT2</i> and <i>MAGED1</i>—are shown in red. Genes depicted in blue are deleted in a subset of subjects 1–4. Genes depicted in gray were not deleted in subjects 1–4.</p