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

BMC Medical Genetics

Michael V Zaragoza²  Gary S Feldman⁴  Renius Owen⁵  Mei Peng⁵  Tim Wood¹  Julie Simon³  Lauren S Marshall³ 

[1]Greenwood Genetic Center, Biochemical Genetics Laboratory, Greenwood, SC, USA

[2]University of California, Irvine School of Medicine, 2042 Hewitt Hall, Irvine, CA, 92697-3940, USA

[3]Pediatrics Department, Genetics & Metabolism Division, University of California, Irvine, Irvine, CA, USA

[4]Stramski Children’s Developmental Center, Miller Children's Hospital, Long Beach, CA, USA

[5]Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA

关键词: X-linked mental retardation;    Mucopolysaccharidosis II;    Fragile X syndrome;    Chromosome deletion;    X-inactivation;    X chromosome;   

Others  :  1177704
DOI  :  10.1186/1471-2350-14-49

 received in 2012-09-04, accepted in 2013-04-25,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Marshall et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Neufeld EF, Muenzer J: The mucopolysaccharidoses. In The Metabolic and Molecular Bases of Inherited Disease. Volume 3. 8th edition. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 2001:3421-3452.
• [2]Beck M, Steglich C, Zabel B, Dahl N, Schwinger E, Hopwood JJ, Gal A: Deletion of the Hunter gene and both DXS466 and DXS304 in a patient with mucopolysaccharidosis type II. Am J Med Genet 1992, 44:100-103.
• [3]Flomen RH, Green PM, Bentley DR, Giannelli F, Green EP: Detection of point mutations and a gross deletion in six Hunter syndrome patients. Genomics 1992, 13:543-550.
• [4]Timms KM, Huckett LE, Belmont JW, Shapira SK, Gibbs RA: DNA deletion confined to the iduronate-2-sulfatase promoter abolishes IDS gene expression. Hum Mutat 1998, 11:121-126.
• [5]Verkerk AJMH, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DPA, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang F, Eussen BE, van Ommen GJB, Blonden LAJ, Riggins GJ, Chastain JL, Kunst CB, Galjaard H, Caskey CT, Nelson DL, Oostra BA, Warren ST: Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991, 65:905-914.
• [6]Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K, Baker E, Warren ST, Schlessinger D, Sutherland GR, Richards RI: Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CGG)n. Science 1991, 252:1711-1714.
• [7]Gedeon AK, Baker E, Robinson H, Partington MW, Gross B, Manca A, Korn B, Poustka A, Yu S, Sutherland GR, Mulley JC: Fragile-X syndrome without CCG amplification has an FMR1 deletion. Nat Genet 1992, 1:341-344.
• [8]Meljer H, de Graaff E, Merckx DML, Jongbloed RJE, de Die-Smulders CEM, Engelen JJM, Fryns JP, Curfs PMG, Oostra BA: A deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene causes the clinical phenotype of the fragile X syndrome. Hum Molec Genet 1994, 3:615-620.
• [9]Quan F, Grompe M, Jakobs P, Popovich BW: Spontaneous deletion in the FMR1 gene in a patient with fragile X syndrome and cherubism. Hum Molec Genet 1995, 4:1681-1684.
• [10]Quan F, Zonana J, Gunter K, Peterson KL, Magenis RE, Popovich BW: An atypical case of fragile X syndrome caused by a deletion that includes the FMR1 gene. Am J Hum Genet 1995, 56:1042-1051.
• [11]Clarke JT, Wilson PJ, Morris CP, Hopwood JJ, Richards RI, Sutherland GR, Ray PN: Characterization of a deletion at Xq27-q28 associated with unbalanced inactivation of the nonmutant X chromosome. Am J Hum Genet 1992, 51:316-322.
• [12]Probst FJ, Roeder ER, Enciso VB, Ou Z, Cooper ML, Eng P, Li J, Gu Y, Stratton RF, Chinault AC, Shaw CA, Sutton VR, Cheung SW, Nelson DL: Chromosomal Microarray Analysis (CMA) detects a large X chromosome deletion including FMR1, FMR2, and IDS in a female patient with mental retardation. Am J Med Gen 2007, 143A:1358-1365.
• [13]Dahl N, Hu LJ, Chery M, Fardeau M, Gilgenkrantz F, Nivelon-Chevallier A, Sidaner-Noisette I, Mugneret F, Gouyon JB, Gal A: Kioschis P, d'Urso M, Mandel JL: Myotubular myopathy in a girl with a deletion at Xq27-q28 and unbalanced X inactivation assigns the MTM1 gene to a 600-kb region. Am J Hum Genet 1995, 56:1108-1115.
• [14]Schmidt M, Certoma A, Du Sart D, Kalitsis P, Leversha M, Fowler K, Sheffield L, Jack I, Danks DM: Unusual X chromosome inactivation in a mentally retarded girl with an interstitial deletion Xq27: implications for the fragile X syndrome. Hum Genet 1990, 84:347-352.
• [15]Schmidt M: Do sequences in Xq27.3 play a role in X inactivation? Am J Med Genet 1992, 43:279-281.
• [16]Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW: Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 1992, 51:1229-1239.
• [17]Brusius-Facchin AC, De Souza CF, Schwartz IV, Riegel M, Melaragno MI, Correia P, Moraes LM, Llerena J Jr, Giugliani R, Leistner-Segal S: Severe phenotype in MPS II patients associated with a large deletion including contiguous genes. Am J Med Genet A 2012, 158A:1055-1059.
• [18]Clarke JT, Willard HF, Teshima I, Chang PL, Skomorowski MA: Hunter disease (mucopolysacchardisosis type II) in a karyotypically normal girl. Clin Genet 1990, 37:355-362.
• [19]Saul RA, Tarleton JC: FMR1-Related Disorders. 1998 Jun 16 [Updated 2012 Apr 26]. In GeneReviews™ [Internet]. Edited by Pagon RA, Bird TD, Dolan CR. Seattle (WA): University of Washington, Seattle; 1993. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1384/ webcite
• [20]Parrish JE, Scheuerle AE, Lewis RA, Levy ML, Nelson DL: Selection against mutant alleles in blood leukocytes is a consistent feature in Incontinentia Pigmenti type 2. Hum Mol Genet 1996, 5:1777-1783.
• [21]Aradhya S, Woffendin H, Jakins T, Bardaro T, Esposito T, Smahi A, Shaw C, Levy M, Munnich A, D'Urso M, Lewis RA, Kenwrick S, Nelson DL: A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations. Hum Mol Genet 2001, 10:2171-2179.
• [22]Fusco F, Bardaro T, Fimiani G, Mercadante V, Miano MG, Falco G, Israël A, Courtois G, D'Urso : Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappaB activation. Hum Mol Genet 2004, 13:1763-1773.
• [23]Gale RE, Wheadon H, Boulos P, Linch DC: Tissue specificity of X-chromosome inactivation patterns. Blood 1994, 83:2899-2905.
• [24]Sharp A, Robinson D, Jacobs P: Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet 2000, 107:343-349.
• [25]Carrel L, Willard HF: X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 2005, 434:400-404.
• [26]Lubs HA, Stevenson RE, Schwartz CE: Fragile X and X-linked intellectual disability: four decades of discovery. Am J Hum Genet 2012, 90:579-590.
• [27]Ropers HH, Hamel BCJ: X-linked mental retardation. Nat Rev Genet 2005, 6:46-57.
• [28]Hahn KA, Salomons GS, Tackels-Horne D, Wood TC, Taylor HA, Schroer RJ, Lubs HA, Jakobs C, Olson RL, Holden KR, Stevenson RE, Schwartz CE: X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28. Am J Hum Genet 2002, 70:1349-1356.
• [29]Rosenberg EH, Almeida LS, Kleefstra T, deGrauw RS, Yntema HG, Bahi N, Moraine C, Ropers HH, Fryns JP, deGrauw TJ, Jakobs C, Salomons GS: High prevalence of SLC6A8 deficiency in X-linked mental retardation. Am J Hum Genet 2004, 75:97-105.
• [30]Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY: Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999, 23:185-188.
• [31]D'Adamo P, Menegon A, Lo Nigro C, Grasso M, Gulisano M, Tamanini F, Bienvenu T, Gedeon AK, Oostra B, Wu SK, Tandon A, Valtorta F, Balch WE, Chelly J, Toniolo D: Mutations in GDI1 are responsible for X-linked non-specific mental retardation. Nat Genet 1998, 19:134-139.
• [32]Takano K, Liu D, Tarpey P, Gallant E, Lam A, Witham S, Alexov E, Chaubey A, Stevenson RE, Schwartz CE, Board PG, Dulhunty AF: An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity. Hum Molec Genet 2012, 21:4497-4507.
• [33]Huang L, Jolly LA, Willis-Owen S, Gardner A, Kumar R, Douglas E, Shoubridge C, Wieczorek D, Tzschach A, Cohen M, Hackett A, Field M, Froyen G, Hu H, Haas SA, Ropers HH, Kalscheuer VM, Corbett MA, Gecz J: A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability. Am J Hum Genet 2012, 91:694-702.
• [34]Giannandrea M, Bianchi V, Mignogna ML, Sirri A, Carrabino S, D'Elia E, Vecellio M, Russo S, Cogliati F, Larizza L, Ropers HH, Tzschach A, Kalscheuer V, Oehl-Jaschkowitz B, Skinner C, Schwartz CE, Gecz J, Van Esch H, Raynaud M, Chelly J, de Brouwer AP, Toniolo D, D'Adamo P: Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly. Am J Hum Genet 2010, 86:185-195.
• [35]Laporte J, Hu LJ, Kretz C, Mandel JL, Kioschis P, Coy JF, Klauck SM, Poustka A, Dahl N: A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat Genet 1996, 13:175-182.
• [36]Marozzi A, Manfredini E, Tibiletti MG, Furlan D, Villa N, Vegetti W, Crosignani PG, Ginelli E, Meneveri R, Dalprà L: Molecular definition of Xq common-deleted region in patients affected by premature ovarian failure. Hum Genet 2000, 107:304-311.
• [37]Gu W, Zhang F, Lupski JR: Mechanisms for human genomic rearrangements. Pathogenetics 2008, 1:4. BioMed Central Full Text