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

Marshall LS, Simon J, Wood T, Peng M, Owen R, Feldman GS, Zaragoza MV - BMC Med. Genet. (2013)

Bottom Line: Gene deletions of the Xq27-28 region are less frequently found in either condition with rare reports in females.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.

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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.

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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.
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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.

Mentions: Chromosome and DNA studies found an abnormal karyotype with a deletion on the X chromosome. Fragile X PCR revealed only one unmethylated FMR1 allele within the normal size range (~30 CGG repeats), and Southern Blot analysis confirmed a deletion of the FMR1 region on one X chromosome. BAC array showed a ~10.6 megabase deletion at Xq27.3q28 (144,270,614-154,845,961 bp) encompassed within BAC clones CTD-3109C8 to CTD-2341N11 (Figure 2). This deletion resulted in hemizygosity for 113 RefSeq genes including the FMR1 and iduronate 2-sulfatase (IDS) genes which are associated with Fragile X syndrome (FXS) and Hunter syndrome, respectively (Figure 3). OMIM disease-associated genes within the deletion region included: FMR1, AFF2 (FMR2), IDS, MAMLD1, MTM1, NSDHL, ATP2B3, FAM58A, SLC6A8, ABCD1, L1CAM, AVPR2, NAA10, HCFC1, MECP2, OPN1LW, OPN1MW, FLNA, EMD, RPL10, TAZ, GDI1, G6PD, IKBKG (NEMO), DKC1, F8, RAB39B, CLIC2, and TMLHE.


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

Marshall LS, Simon J, Wood T, Peng M, Owen R, Feldman GS, Zaragoza MV - BMC Med. Genet. (2013)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3643848&req=5

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.
Mentions: Chromosome and DNA studies found an abnormal karyotype with a deletion on the X chromosome. Fragile X PCR revealed only one unmethylated FMR1 allele within the normal size range (~30 CGG repeats), and Southern Blot analysis confirmed a deletion of the FMR1 region on one X chromosome. BAC array showed a ~10.6 megabase deletion at Xq27.3q28 (144,270,614-154,845,961 bp) encompassed within BAC clones CTD-3109C8 to CTD-2341N11 (Figure 2). This deletion resulted in hemizygosity for 113 RefSeq genes including the FMR1 and iduronate 2-sulfatase (IDS) genes which are associated with Fragile X syndrome (FXS) and Hunter syndrome, respectively (Figure 3). OMIM disease-associated genes within the deletion region included: FMR1, AFF2 (FMR2), IDS, MAMLD1, MTM1, NSDHL, ATP2B3, FAM58A, SLC6A8, ABCD1, L1CAM, AVPR2, NAA10, HCFC1, MECP2, OPN1LW, OPN1MW, FLNA, EMD, RPL10, TAZ, GDI1, G6PD, IKBKG (NEMO), DKC1, F8, RAB39B, CLIC2, and TMLHE.

Bottom Line: Gene deletions of the Xq27-28 region are less frequently found in either condition with rare reports in females.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.

View Article: PubMed Central - HTML - PubMed

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.

Show MeSH
Related in: MedlinePlus