Xq28 duplication overlapping the int22h-1/int22h-2 region and including RAB39B and CLIC2 in a family with intellectual and developmental disability.
Duplications involving terminal Xq28 are a known cause of intellectual disability (ID) in males and in females with unfavorable X-inactivation patterns. Within Xq28, functional disomy of MECP2 causes a severe ID syndrome, however the dosage sensitivity of other Xq28 duplicated genes is less certain. Duplications involving the int22h-1/int22h-2 LCR-flanked region in distal Xq28 have recently been linked to a novel ID-associated phenotype. While evidence for the dosage sensitivity of this region is emerging, the phenotypic contribution of individual genes within the int22h-1/int22h-2-flanked region has yet to be determined. We report a familial case of a novel 774 kb Xq28-qter duplication, detected by cytogenomic microarray analysis, that partially overlaps the int22h-1/int22h-2-flanked region. This duplication and a 570 kb Xpter-p22.33 loss within the pseudoautosomal region were identified in three siblings, one female and two males, who presented with developmental delays/intellectual disability, mild dysmorphic features and short stature. Although unconfirmed, these results are suggestive of maternal inheritance of a recombinant X. We compare our clinical findings to patients with int22h-1/int22h-2-mediated duplications and discuss the potential pathogenicity of genes within the duplicated region, including those within the shared region of overlap, RAB39B and CLIC2.
Cytogenetics and Genomic Microarray, ARUP Laboratories, Salt Lake City, Utah; Department of Pathology, University of Utah, Salt Lake City, Utah.
Erica F
EF
Andersen
Erin E
EE
Baldwin
Sara
S
Ellingwood
Rosemarie
R
Smith
Allen N
AN
Lamb
D018118:Chloride Channels / Q000235:genetics*; D058674:Chromosome Duplication; D041321:Chromosomes, Human, X; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D035781:Siblings; D020691:rab GTP-Binding Proteins / Q000235:genetics*
C108828:CLIC2 protein, human; D018118:Chloride Channels; C547812:Rab39B protein, human; D020691:rab GTP-Binding Proteins
CLIC2; RAB39B; Xp22.33 deletion; Xq28 duplication; int22h