BMC Medical Genetics
A 5.8 Mb interstitial deletion on chromosome Xq21.1 in a boy with intellectual disability, cleft palate, hearing impairment and combined growth hormone deficiency
M. Bozzola2  E. Bozzola1  I. Fusco3  C. Meazza2  S. Pagani2  C. Gertosio4  M. Giordano3 
[1]Department of Pediatric Medicine, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
[2]Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
[3]Laboratory of Genetics, Department of Health Sciences, University of Eastern Piedmont, Via Solaroli 17, Novara, 28100, Italy
[4]Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
关键词: Intellectual disability;    Pituitary hormone deficiency;    Short stature;    Xq21.1 deletion;   
Others  :  1223131
DOI  :  10.1186/s12881-015-0220-z
 received in 2015-03-02, accepted in 2015-08-19, published in 16
【 摘 要 】


Deletions of the long arm of chromosome X in males are a rare cause of X-linked intellectual disability. Here we describe a patient with an interstitial deletion of the Xq21.1 chromosome.

Case presentation

In a 15 year boy, showing intellectual disability, short stature, hearing loss and dysmorphic facial features, a deletion at Xq21.1 was identified by array-CGH. This maternally inherited 5.8 Mb rearrangement encompasses 14 genes, including BRWD3 (involved in X-linked intellectual disability), TBX22 (a gene whose alterations have been related to the presence of cleft palate), POU3F4 (mutated in X-linked deafness) and ITM2A (a gene involved in cartilage development).


Correlation between the clinical findings and the function of gene mapping within the deleted region confirms the causative role of this microrearrangement in our patient and provides new insight into a gene possibly involved in short stature.

【 授权许可】

2015 Giordano et al.

【 预 览 】
Files Size Format View
20150901020407747.pdf 1230KB PDF download
Fig. 4. 59KB Image download
Fig. 3. 25KB Image download
Fig. 2. 22KB Image download
Fig. 1. 61KB Image download
【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

【 参考文献 】
  • [1]Cremers FP, Sankila EM, Brunsmann F, Jay M, Jay B, Wright A, Pinckers AJ, Schwartz M, van de Pol DJ, Wieringa B, de la Chapelle A, Pawlowitzki IH, Ropers HH. Deletions in patients with classical choroideremia vary in size from 45 kb to several megabases. Am J Hum Genet. 1990; 47:622-8.
  • [2]Plenge RM, Stevenson RA, Lubs HA, Schwartz CE, Willard HF. Skewed X-chromosome inactivation is a common feature of X-linked mental retardation disorders. Am J Hum Genet. 2002; 71:168-73.
  • [3]Lugtenberg D, Veltman JA, van Bokhoven H. High-resolution genomic microarrays for X-linked mental retardation. Genet Med. 2007; 9:560-5.
  • [4]Isrie M, Foryen G, Devirendt K, de Ravel T, Fryns JP, Vermeesch JR, Van Esch H. Sporadic patients with intellectual disability: Contribution of X-chromosome copy number variants. Eur J Med Genet. 2012; 55:577-85.
  • [5]Andreou AM, Pauws E, Jones MC, Singh MK, Bussen M, Doudney K, Moore GE, Kispert A, Brosens JJ, Stanier P. TBX22 missense mutations found in patients with X-linked cleft palate affect DNA binding, sumoylation, and transcriptional repression. Am J Hum Genet. 2007; 81:700-12.
  • [6]Kaewkhampa A, Jotikasthira D, Malaivijitnond S, Kantaputra P. TBX22 mutation associated with cleft lip/palate, hypodontia, and limb anomaly. Cleft Palate Craniofac J. 2012; 49:240-4.
  • [7]Pauws E, Peskett E, Boissin C, Hoshino A, Mengrelis K, Carta E, Abruzzo MA, Lees M, Moore GE, Erickson RP, Stanier P. X-linked CHARGE-Like Abruzzo-Erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations. Clin Genet. 2013; 83:352-8.
  • [8]Raviv D, Dror AA, Avraham KB. Hearing loss: a common disorder caused by many rare alleles. Ann N Y Acad Sci. 2010; 1214:168-79.
  • [9]de Kok YJ, Vossenaar ER, Cremers CW, Dahl N, Laporte J, Hu LJ, Lacombe D, Fischel-Ghodsian N, Friedman RA, Parnes LS, Thorpe P, Bitner-Glindzicz M, Pander HJ, Heilbronner H, Graveline J, den Dunnen JT, Brunner HG, Ropers HH, Cremers FP. Identification of a hot spot for microdeletions in patients with X-linked deafness type 3 (DFN3) 900 kb proximal to the DFN3 gene POU3F4. Hum Mol Genet. 1996; 5:1229-35.
  • [10]Rush ET, Schaefer GB. Identification of an X-linked deletion syndrome through comparative genomic hybridization microarray. Semin Pediatr Neurol. 2010; 17:51-3.
  • [11]Vore AP, Chang EH, Hoppe JE, Butler MG, Forrester S, Schneider MC, Smith LL, Burke DW, Campbell CA, Smith RJ. Deletion of and novel missense mutation in POU3F4 in 2 families segregating X-linked nonsyndromic deafness. Arch Otolaryngol Head Neck Surg. 2005; 131:1057-63.
  • [12]Marlin S, Moizard MP, David A, Chaissang N, Raynaud M, Jonard L, Feldmann D, Loundon N, Denoyelle F, Toutain A. Phenotype and genotype in females with POU3F4 mutations. Clin Genet. 2009; 76:558-63.
  • [13]Field M, Tarpey PS, Smith R, Edkins S, O'Meara S, Stevens C, Tofts C, Teague J, Butler A, Dicks E, Barthorpe S, Buck G, Cole J, Gray K, Halliday K, Hills K, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Varian J, West S, Widaa S, Mallya U, Wooster R, Moon J, Luo Y, Hughes H, Shaw M, Friend KL, Corbett M, Turner G, Partington M, Mulley J, Bobrow M, Schwartz C, Stevenson R, Gecz J, Stratton MR, Futreal PA, Raymond FL. Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly. Am J Hum Genet. 2007; 81:367-74.
  • [14]Grotto S, Drouin-Garraud V, Ounap K, Puusepp-Benazzouz H, Schuurs-Hoeijmakers J, Le Meur N, Chambon P, Fehrenbach S, van Bokhoven H, Frébourg T, de Brouwer AP, Saugier-Veber P. Clinical assessment of five patients with BRWD3 mutation ad Xq21.1 gives further evidence for mild to moderate intellectual disability and macrocephaly. Eur J Med Genet. 2014; 57:200-6.
  • [15]Ozturk N, VanVickle-Chavez SJ, Akileswaran L, Van Gelder RN, Sancar A. Ramshackle (Brwd3) promotes light-induced ubiquitylation of Drosophila Cryptochrome by DDB1-CUL4-ROC1 E3 ligase complex. Proc Natl Acad Sci USA. 2013; 110:4980-5.
  • [16]Jarome TJ, Kwapis JL, Hallengren JJ, Wilson SM, Helmstetter FJ. The ubiquitin-specific protease 14 (USP14) is a critical regulator of long-term memory formation. Learn Mem. 2013; 21:9-13.
  • [17]Tarpey PS, Raymond FL, O'Meara S, Edkins S, Teague J, Butler A, Dicks E, Stevens C, Tofts C, Avis T, Barthorpe S, Buck G, Cole J, Gray K, Halliday K, Harrison R, Hills K, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Varian J, West S, Widaa S, Mallya U, Moon J, Luo Y, Holder S, Smithson SF, Hurst JA, Clayton-Smith J, Kerr B, Boyle J, Shaw M, Vandeleur L, Rodriguez J, Slaugh R, Easton DF, Wooster R, Bobrow M, Srivastava AK, Stevenson RE, Schwartz CE, Turner G, Gecz J, Futreal PA, Stratton MR, Partington M. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am J Hum Genet. 2007; 80:345-52.
  • [18]Pfäffle R, Klammt J. Pituitary transcription factors in the aetiology of combined pituitary hormone deficiency. Best Pract Res Clin Endocrinol Metab. 2011; 25:43-60.
  • [19]Yokoyama Y, Narahara K, Tsuji K, Moriwake T, Kanzaki S, Murakami M, Namba H, Ninomiya S, Higuchi J, Seino T. Growth hormone deficiency and empty sella syndrome in a boy with dup(X)(q13.3-q21.2). Am J Med Genet. 1992; 42:660-4.
  • [20]Shapira M, Dar H, Bar-El H, Bar-Nitzan N, Even L, Borochowitz Z. Inherited inverted duplication of X chromosome in a male: report of a patient and review of the literature. Am J Med Genet. 1997; 72:409-14.
  • [21]Sismani C, Donoghue J, Alexandrou A, Karkaletsi M, Christopoulou S, Konstantinidou AE, Livanos P, Patsalis PC, Velissariou V. A prenatally ascertained, maternally inherited 14.8 Mb duplication of chromosomal bands Xp13.23-q21.31 associated with multiple congenital abnormalities in a male fetus. Gene. 2013; 530:138-42.
  • [22]Van den Plas D, Merregaert J. In vitro studies on Itm2a reveal its involvement in early stages of the chondrogenic differentiation pathway. Biol Cell. 2004; 96:463-70.
  • [23]Boeuf S, Börger M, Hennig T, Winter A, Kasten P, Richter W. Enhanced ITM2A expression inhibits chondrogenic differentiation of mesenchymal stem cells. Differentiation. 2009; 78:108-15.
  下载次数:8次 浏览次数:15次