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

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

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

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

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

A Multicenter Analysis of Abnormal Chromosomal Microarray Findings in Congenital Heart Disease

Background Chromosomal microarray analysis (CMA) provides an opportunity to understand genetic causes of congenital heart disease (CHD). The methods for describing cardiac phenotypes in patients with CMA abnormalities have been inconsistent, which may complicate clinical interpretation of abnormal testing results and hinder a more complete understanding of genotype–phenotype relationships. Methods and Results Patients with CHD and abnormal clinical CMA were accrued from 9 pediatric cardiac centers. Highly detailed cardiac phenotypes were systematically classified and analyzed for their association with CMA abnormality. Hierarchical classification of each patient into 1 CHD category facilitated broad analyses. Inclusive classification allowing multiple CHD types per patient provided sensitive descriptions. In 1363 registry patients, 28% had genomic disorders with well‐recognized CHD association, 67% had clinically reported copy number variants (CNVs) with rare or no prior CHD association, and 5% had regions of homozygosity without CNV. Hierarchical classification identified expected CHD categories in genomic disorders, as well as uncharacteristic CHDs. Inclusive phenotyping provided sensitive descriptions of patients with multiple CHD types, which occurred commonly. Among CNVs with rare or no prior CHD association, submicroscopic CNVs were enriched for more complex types of CHD compared with large CNVs. The submicroscopic CNVs that contained a curated CHD gene were enriched for left ventricular obstruction or septal defects, whereas CNVs containing a single gene were enriched for conotruncal defects. Neuronal‐related pathways were over‐represented in single‐gene CNVs, including top candidate causative genes NRXN3, ADCY2, and HCN1. Conclusions Intensive cardiac phenotyping in multisite registry data identifies genotype–phenotype associations in CHD patients with abnormal CMA

Delineation of a novel neurodevelopmental syndrome associated with PAX5 haploinsufficiency.

PAX5 is a transcription factor associated with abnormal posterior midbrain and cerebellum development in mice. PAX5 is highly loss-of-function intolerant and missense constrained, and has been identified as a candidate gene for autism spectrum disorder (ASD). We describe 16 individuals from 12 families who carry deletions involving PAX5 and surrounding genes, de novo frameshift variants that are likely to trigger nonsense-mediated mRNA decay, a rare stop-gain variant, or missense variants that affect conserved amino acid residues. Four of these individuals were published previously but without detailed clinical descriptions. All these individuals have been diagnosed with one or more neurodevelopmental phenotypes including delayed developmental milestones (DD), intellectual disability (ID), and/or ASD. Seizures were documented in four individuals. No recurrent patterns of brain magnetic resonance imaging (MRI) findings, structural birth defects, or dysmorphic features were observed. Our findings suggest that PAX5 haploinsufficiency causes a neurodevelopmental disorder whose cardinal features include DD, variable ID, and/or ASD