Interstitial microduplication at 2p11.2 in a patient with syndromic intellectual disability: 30-year follow-up

Molecular Cytogenetics

Hyung-Goo Kim²  Lawrence C Layman⁵  Saadullah Khan³  Reinhard Ullmann¹  Kyung Ran Jun⁴ 

[1] Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany;Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics and Gynecology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, Georgia;Department of Biotechnology & Genetic engineering, Kohat University of Science & Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan;Department of Laboratory Medicine, Inje University Haeundae Paik Hospital, Busan, South Korea;Neuroscience Program, Medical College of Georgia, Georgia Regents University, Augusta, Georgia

关键词: VAMP8;    2p11.2;    RNF181;    Recurrent infection;    Intellectual disability;    Duplication;    Copy number variation;    CAPG;    Array CGH;   

Others  :  1149850
DOI  :  10.1186/1755-8166-7-52

 received in 2014-05-08, accepted in 2014-06-20,  发布年份 2014

【 摘 要 】

Background

Copy number variations at 2p11.2 have been rare and to our knowledge, no abnormal phenotype with an interstitial 2p11.2 duplication has yet been reported. Here we report the first case with syndromic intellectual disability associated with microduplication at 2p11.2.

Results

We revisited a white female subject with a chromosome translocation, t(8;10)(p23;q23)mat and a 10q telomeric deletion suspected by G-banding 30 years ago. This female with severe intellectual disability, no speech, facial dysmorphism, intractable epilepsy, recurrent infection, and skeletal abnormalities has been observed from the birth until her death. The karyotype analysis reconfirmed the previously reported chromosome translocation with a revision as 46,XX,t(8;10)(p23.3;q23.2)mat by adding more detail in chromosomal sub-bands. The array comparative genomic hybridization, however, did not detect the 10q terminal deletion originally reported, but instead, revealed a 390 kb duplication at 2p11.2; 46,XX,t(8;10)(p23.3;q23.2)mat.arr[hg 19] 2p11.2(85469151x2,85474356-85864257x3,85868355x2). This duplication region was confirmed by real-time quantitative PCR and real-time reverse transcriptase quantitative PCR.

Conclusions

We suggest three positional candidate genes for intellectual disability and recurrent infection based upon gene function and data from real-time reverse transcriptase quantitative PCR—VAMP8 and RNF181 for intellectual disability and CAPG for recurrent infection.

【 授权许可】

   
2014 Jun et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Larson LM, Wasdahl WA, Saumur JH, Coleman ML, Hall JG, Dolan CR, Schutta CJ: Familial reciprocal translocation, t(2;10)(p24;q26), resulting in duplication 2p and delection 10q. Clin Genet 1982, 21:187-195.
• [2]Lurie IW, Ilyina HG, Gurevich DB, Rumyantseva NV, Naumchik IV, Castellan C, Hoeller A, Schinzel A: Trisomy 2p: analysis of unusual phenotypic findings. Am J Med Genet 1995, 55:229-236.
• [3]Atik T, Durmaz B, Yorganci OU, Cogulu O, Kioutsouk M, Ozkinay F: Partial trisomy 2p24-- pter and monosomy 18q22.1- qter resulting from parental translocation. Genet Couns 2013, 24:179-184.
• [4]Siffroi JP, Molina-Gomez D, Viguie F, Nessmann C, Dadoune JP: Prenatal diagnosis of partial 2p trisomy by ‘de novo’ duplication 2p (13.1– 21). Confirmation by FISH. Prenat Diagn 1994, 14:1097-1099.
• [5]Aviram-Goldring A, Fritz B, Bartsch C, Steuber E, Daniely M, Lev D, Chaki R, Barkai G, Frydman M, Rehder H: Molecular cytogenetic studies in three patients with partial trisomy 2p, including CGH from paraffin-embedded tissue. Am J Med Genet 2000, 91:74-82.
• [6]Thangavelu M, Frolich G, Rogers D: Partial duplication 2p as the sole abnormality in two cases with anencephaly. Am J Med Genet A 2004, 124A:170-172.
• [7]Blassnig-Ezeh A, Bandelier C, Frühmesser A, Revencu N, Krabichler B, Beauloye V, Ravoet M, Fauth C, Zschocke J, Simma B, Kotzot D: Severe growth retardation, delayed bone age, and facial dysmorphism in two patients with microduplications in 2p16 – p22. Am J Med Genet A 2013, 161A:3176-3181.
• [8]Dodé C, Levilliers J, Dupont JM, De Paepe A, Le Dû N, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pêcheux C, Le Tessier D, Cruaud C, Delpech M, Speleman F, Vermeulen S, Amalfitano A, Bachelot Y, Bouchard P, Cabrol S, Carel JC, Delemarre van de Waal H, Goulet-Salmon B, Kottler ML, Richard O, Sanchez-Franco F, Saura R, Young J, Petit C, Hardelin JP: Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 2003, 33:463-465.
• [9]Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, van der Vliet WA, Huys EH, de Jong PJ, Hamel BC, Schoenmakers EF, Brunner HG, Veltman JA, van Kessel AG: Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 2004, 36:955-957.
• [10]Chieri P, Iölster N: Monosomy 10qter due to a balanced maternal translocation: t(10;8)(q23;p23). Clin Genet 1983, 24:147-150.
• [11]Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SF, Hakonarson H, Bucan M: PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res 2007, 17:1665-1674.
• [12]Kidd JM, Cooper GM, Donahue WF, Hayden HS, Sampas N, Graves T, Hansen N, Teague B, Alkan C, Antonacci F, Haugen E, Zerr T, Yamada NA, Tsang P, Newman TL, Tüzün E, Cheng Z, Ebling HM, Tusneem N, David R, Gillett W, Phelps KA, Weaver M, Saranga D, Brand A, Tao W, Gustafson E, McKernan K, Chen L, Malig M, et al.: Mapping and sequencing of structural variation from eight human genomes. Nature 2008, 453:56-64.
• [13]Pang AW, MacDonald JR, Pinto D, Wei J, Rafiq MA, Conrad DF, Park H, Hurles ME, Lee C, Venter JC, Kirkness EF, Levy S, Feuk L, Scherer SW: Towards a comprehensive structural variation map of an individual human genome. Genome Biol 2010, 11:R52.
• [14]Wheeler DA, Srinivasan M, Egholm M, Shen Y, Chen L, McGuire A, He W, Chen YJ, Makhijani V, Roth GT, Gomes X, Tartaro K, Niazi F, Turcotte CL, Irzyk GP, Lupski JR, Chinault C, Song XZ, Liu Y, Yuan Y, Nazareth L, Qin X, Muzny DM, Margulies M, Weinstock GM, Gibbs RA, Rothberg JM: The complete genome of an individual by massively parallel DNA sequencing. Nature 2008, 452:872-876.
• [15]Mills RE, Luttig CT, Larkins CE, Beauchamp A, Tsui C, Pittard WS, Devine SE: An initial map of insertion and deletion (INDEL) variation in the human genome. Genome Res 2006, 16:1182-1190.
• [16]Tzschach A, Graul-Neumann LM, Konrat K, Richter R, Ebert G, Ullmann R, Neitzel H: Interstitial deletion 2p11.2-p12: report of a patient with mental retardation and review of the literature. Am J Med Genet A 2009, 149A:242-245.
• [17]Barber JC, Thomas NS, Collinson MN, Dennis NR, Liehr T, Weise A, Belitz B, Pfeiffer L, Kirchhoff M, Krag-Olsen B, Lundsteen C: Segmental haplosufficiency: transmitted deletions of 2p12 include a pancreatic regeneration gene cluster and have no apparent phenotypic consequences. Eur J Hum Genet 2005, 13:283-291.
• [18]MacDonald BT, Tamai K, He X: Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009, 17:9-26.
• [19]Graham TA, Clements WK, Kimelman D, Xu W: Crystal structure of a beta-catenin/Tcf complex. Cell 2000, 103:885-896.
• [20]de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE: Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 2012, 367:1921-1929.
• [21]Tai HC, Schuman EM: Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction. Nat Rev Neurosci 2008, 9:826-838.
• [22]Gloeckner CJ, Boldt K, Schumacher A, Roepman R, Ueffing M: A novel tandem affinity purification strategy for the efficient isolation and characterisation of native protein complexes. Proteomics 2007, 7:4228-4234.
• [23]Ikeda M, Hikita T, Taya S, Uraguchi-Asaki J, Toyo-oka K, Wynshaw-Boris A, Ujike H, Inada T, Takao K, Miyakawa T, Ozaki N, Kaibuchi K, Iwata N: Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia. Hum Mol Genet 2008, 17:3212-3222.
• [24]Brophy TM, Raab M, Daxecker H, Culligan KG, Lehmann I, Chubb AJ, Treumann A, Moran N: RN181, a novel ubiquitin E3 ligase that interacts with the KVGFFKR motif of platelet integrin alpha(IIb)beta3. Biochem Biophys Res Commun 2008, 369:1088-1093.
• [25]Froyen G, Corbett M, Vandewalle J, Jarvela I, Lawrence O, Meldrum C, Bauters M, Govaerts K, Vandeleur L, Van Esch H, Chelly J, Sanlaville D, van Bokhoven H, Ropers HH, Laumonnier F, Ranieri E, Schwartz CE, Abidi F, Tarpey PS, Futreal PA, Whibley A, Raymond FL, Stratton MR, Fryns JP, Scott R, Peippo M, Sipponen M, Partington M, Mowat D, Field M, et al.: Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation. Am J Hum Genet 2008, 82:432-443.
• [26]Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N: Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998, 392:605-608.
• [27]Kishino T, Lalande M, Wagstaff J: UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 1997, 15:70-73.
• [28]Basel-Vanagaite L, Dallapiccola B, Ramirez-Solis R, Segref A, Thiele H, Edwards A, Arends MJ, Miró X, White JK, Désir J, Abramowicz M, Dentici ML, Lepri F, Hofmann K, Har-Zahav A, Ryder E, Karp NA, Estabel J, Gerdin AK, Podrini C, Ingham NJ, Altmüller J, Nürnberg G, Frommolt P, Abdelhak S, Pasmanik-Chor M, Konen O, Kelley RI, Shohat M, Nürnberg P, et al.: Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome. Am J Hum Genet 2012, 91:998-1010.
• [29]Margolin DH, Kousi M, Chan YM, Lim ET, Schmahmann JD, Hadjivassiliou M, Hall JE, Adam I, Dwyer A, Plummer L, Aldrin SV, O’Rourke J, Kirby A, Lage K, Milunsky A, Milunsky JM, Chan J, Hedley-Whyte ET, Daly MJ, Katsanis N, Seminara SB: Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. N Engl J Med 2013, 368:1992-2003.
• [30]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, et al.: 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, 80:345-352.
• [31]Nascimento RM, Otto PA, de Brouwer AP, Vianna-Morgante AM: UBE2A, which encodes a ubiquitin-conjugating enzyme, is mutated in a novel X-linked mental retardation syndrome. Am J Hum Genet 2006, 79:549-555.
• [32]Parikh SS, Litherland SA, Clare-Salzler MJ, Li W, Gulig PA, Southwick FS: CapG(-/-) mice have specific host defense defects that render them more susceptible than CapG(+/+) mice to Listeria monocytogenes infection but not to Salmonella enterica serovar Typhimurium infection. Infect Immun 2003, 71:6582-6590.
• [33]Jaworek TJ, Richard EM, Ivanova AA, Giese AP, Choo DI, Khan SN, Riazuddin S, Kahn RA, Riazuddin S: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans. PLoS Genet 2013, 9:e1003774.
• [34]Brenner B, Sánchez-Vega B, Wu SM, Lanir N, Stafford DW, Solera J: A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors. Blood 1998, 92:4554-4559.
• [35]Rost S, Fregin A, Koch D, Compes M, Müller CR, Oldenburg J: Compound heterozygous mutations in the gamma-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors. Br J Haematol 2004, 126:546-549.
• [36]Vanakker OM, Martin L, Gheduzzi D, Leroy BP, Loeys BL, Guerci VI, Matthys D, Terry SF, Coucke PJ, Pasquali-Ronchetti I, De Paepe A: Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity. J Invest Dermatol 2007, 127:581-587.
• [37]Olshen AB, Venkatraman ES, Lucito R, Wigler M: Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 2004, 5:557-572.