Deletion Xq27.3q28 in female patient with global developmental delays and skewed X-inactivation

Abstract

Background: Global developmental delay and mental retardation are associated with X-linked disorders including Hunter syndrome (mucopolysaccharidosis type II) and Fragile X syndrome (FXS). Single nucleotide mutations in the iduronate 2-sulfatase (IDS) gene at Xq28 most commonly cause Hunter syndrome while a CGG expansion in the FMR1 gene at Xq27.3 is associated with Fragile X syndrome. Gene deletions of the Xq27-28 region are less frequently found in either condition with rare reports in females. Additionally, an association between Xq27-28 deletions and skewed X-inactivation of the normal X chromosome observed in previous studies suggested a primary role of the Xq27-28 region in X-inactivation.

Case presentation: We describe the clinical, molecular and biochemical evaluations of a four year-old female patient with global developmental delay and a hemizygous deletion of Xq27.3q28 (144,270,614-154,845,961 bp), a 10.6 Mb region that contains >100 genes including IDS and FMR1. A literature review revealed rare cases with similar deletions that included IDS and FMR1 in females with developmental delay, variable features of Hunter syndrome, and skewed X-inactivation of the normal X chromosome. In contrast, our patient exhibited skewed X-inactivation of the deleted X chromosome and tested negative for Hunter syndrome.

Conclusions: This is a report of a female with a 10.6 Mb Xq27-28 deletion with skewed inactivation of the deleted X chromosome. Contrary to previous reports, our observations do not support a primary role of the Xq27-28 region in X-inactivation. A review of the genes in the deletion region revealed several potential genes that may contribute to the patient's developmental delays, and sequencing of the active X chromosome may provide insight into the etiology of this clinical presentation.

Figure 1

Facial Features. Front (A), three-quarter (B), and profile (C) views of the patient.

Figure 2

Array CGH ratio plot depicts ~10.6 Mb at Xq27.3-q28. Deletion region is highlighted in red. The deletion resulted in hemizygosity for >100 genes including FMR1 and iduronate 2-sulfatase (IDS). BAC probes (CTD-3109C8 to CTD-2341N11) targeting multiple loci were used. Array was performed using Clarisure CGH by Quest Diagnostics.

Figure 3

Schematic of X chromosome and genes in the Xq27.3-q28 region. Region of deletion is highlighted by the red box. Shown are the OMIM-disease associated genes in green and all RefSeq genes in blue within the deletion region of 144,270,614-154,845,961 bp (hg19). Image was adapted from http://genome.ucsc.edu/cgi-bin/hgTracks.