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Published in: BMC Medical Genetics 1/2011

Open Access 01-12-2011 | Research article

Breakpoint characterization of large deletions in EXT1 or EXT2 in 10 Multiple Osteochondromas families

Authors: Ivy Jennes, Danielle de Jong, Kirsten Mees, Pancras CW Hogendoorn, Karoly Szuhai, Wim Wuyts

Published in: BMC Medical Genetics | Issue 1/2011

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Abstract

Background

Osteochondromas (cartilage-capped bone tumors) are by far the most commonly treated of all primary benign bone tumors (50%). In 15% of cases, these tumors occur in the context of a hereditary syndrome called multiple osteochondromas (MO), an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped bone tumors at children's metaphyses. MO is caused by various mutations in EXT1 or EXT2, whereby large genomic deletions (single-or multi-exonic) are responsible for up to 8% of MO-cases.

Methods

Here we report on the first molecular characterization of ten large EXT1- and EXT2-deletions in MO-patients. Deletions were initially indentified using MLPA or FISH analysis and were subsequently characterized using an MO-specific tiling path array, allele-specific PCR-amplification and sequencing analysis.

Results

Within the set of ten large deletions, the deleted regions ranged from 2.7 to 260 kb. One EXT2 exon 8 deletion was found to be recurrent. All breakpoints were located outside the coding exons of EXT1 and EXT2. Non-allelic homologous recombination (NAHR) mediated by Alu-sequences, microhomology mediated replication dependent recombination (MMRDR) and non-homologous end-joining (NHEJ) were hypothesized as the causal mechanisms in different deletions.

Conclusions

Molecular characterization of EXT1- and EXT2-deletion breakpoints in MO-patients indicates that NAHR between Alu-sequences as well as NHEJ are causal and that the majority of these deletions are nonrecurring. These observations emphasize once more the huge genetic variability which is characteristic for MO. To our knowledge, this is the first study characterizing large genomic deletions in EXT1 and EXT2.
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Literature
1.
go back to reference van den Berg H, Kroon HM, Slaar A, Hogendoorn P: Incidence of biopsy-proven bone tumors in children: a report based on the Dutch pathology registration "PALGA". Journal of pediatric orthopedics. 2008, 28 (1): 29-35. 10.1097/BPO.0b013e3181558cb5.CrossRefPubMed van den Berg H, Kroon HM, Slaar A, Hogendoorn P: Incidence of biopsy-proven bone tumors in children: a report based on the Dutch pathology registration "PALGA". Journal of pediatric orthopedics. 2008, 28 (1): 29-35. 10.1097/BPO.0b013e3181558cb5.CrossRefPubMed
3.
go back to reference Schmale GA, Conrad EU, Raskind WH: The natural history of hereditary multiple exostoses. J Bone Joint Surg Br. 1994, 76 (A): 986-992. Schmale GA, Conrad EU, Raskind WH: The natural history of hereditary multiple exostoses. J Bone Joint Surg Br. 1994, 76 (A): 986-992.
4.
go back to reference Bovée J, Hogendoorn P: Multiple Osteochondromas. World Health Organization classification of tumours Pathology and genetics of tumours of soft tissue and bone. Edited by: Fletcher C, Unni K, Mertens F. 2002, Lyon: IARC Press, 360-362. Bovée J, Hogendoorn P: Multiple Osteochondromas. World Health Organization classification of tumours Pathology and genetics of tumours of soft tissue and bone. Edited by: Fletcher C, Unni K, Mertens F. 2002, Lyon: IARC Press, 360-362.
5.
go back to reference Solomon L: Hereditary multiple exostosis. J Bone Joint Surg (Br). 1963, 45: 292-304. Solomon L: Hereditary multiple exostosis. J Bone Joint Surg (Br). 1963, 45: 292-304.
6.
go back to reference Luckert Wicklund C, Pauli RM, Johnston D, Hecht JT: Natural history study of hereditary multiple exostoses. Am J Med Genet. 1995, 55: 43-46. 10.1002/ajmg.1320550113.CrossRef Luckert Wicklund C, Pauli RM, Johnston D, Hecht JT: Natural history study of hereditary multiple exostoses. Am J Med Genet. 1995, 55: 43-46. 10.1002/ajmg.1320550113.CrossRef
7.
go back to reference Ahn J, Lüdecke H, Lindow S, Horton WA, Lee B, Wagner MJ, Horsthemke B, Wells DE: Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nature Genetics. 1995, 11: 137-143. 10.1038/ng1095-137.CrossRefPubMed Ahn J, Lüdecke H, Lindow S, Horton WA, Lee B, Wagner MJ, Horsthemke B, Wells DE: Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nature Genetics. 1995, 11: 137-143. 10.1038/ng1095-137.CrossRefPubMed
8.
go back to reference Stickens D, Clines G, Burbee D, Ramos P, Thomas S, Hogue D, Hecht JT, Lovett M, Evans GA: The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nature Genet. 1996, 14: 25-32. 10.1038/ng0996-25.CrossRefPubMed Stickens D, Clines G, Burbee D, Ramos P, Thomas S, Hogue D, Hecht JT, Lovett M, Evans GA: The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nature Genet. 1996, 14: 25-32. 10.1038/ng0996-25.CrossRefPubMed
9.
go back to reference Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E, Van Hul E, De Boulle K, de Vries BBA, Hendrickx J, Herrygers I, Bossuyt P, Balemans W, Fransen E, Vits L, Coucke P, Nowak NJ, Shows TB, Mallet L, van den Ouweland AMW, McGaughran J, Halley DJJ, Willems PJ: Positional cloning of a gene involved in hereditary multiple exostoses. Human molecular genetics. 1996, 5 (10): 1547-1557. 10.1093/hmg/5.10.1547.CrossRefPubMed Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E, Van Hul E, De Boulle K, de Vries BBA, Hendrickx J, Herrygers I, Bossuyt P, Balemans W, Fransen E, Vits L, Coucke P, Nowak NJ, Shows TB, Mallet L, van den Ouweland AMW, McGaughran J, Halley DJJ, Willems PJ: Positional cloning of a gene involved in hereditary multiple exostoses. Human molecular genetics. 1996, 5 (10): 1547-1557. 10.1093/hmg/5.10.1547.CrossRefPubMed
10.
go back to reference Lüdecke H-J, Ahn J, Lin X, Hill A, Wagner MJ, Schomburg L, Horsthemke B, Wells DE: Genomic organization and promotor structure of the human EXT1 gene. Genomics. 1997, 40: 351-354. 10.1006/geno.1996.4577.CrossRefPubMed Lüdecke H-J, Ahn J, Lin X, Hill A, Wagner MJ, Schomburg L, Horsthemke B, Wells DE: Genomic organization and promotor structure of the human EXT1 gene. Genomics. 1997, 40: 351-354. 10.1006/geno.1996.4577.CrossRefPubMed
11.
go back to reference Clines GA, Ashley JA, Shah S, Lovett M: The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and caenorhabditis elegans. Genome Research. 1997, 7: 359-367.PubMedPubMedCentral Clines GA, Ashley JA, Shah S, Lovett M: The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and caenorhabditis elegans. Genome Research. 1997, 7: 359-367.PubMedPubMedCentral
12.
go back to reference Bovée J, Cleton-Jansen A, Wuyts W, Caethoven G, Taminiau A, Bakker E, Van Hul W, Cornelisse P, Hogendoorn P: EXT mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. AmJHumGenet. 1999, 65: 689-698. Bovée J, Cleton-Jansen A, Wuyts W, Caethoven G, Taminiau A, Bakker E, Van Hul W, Cornelisse P, Hogendoorn P: EXT mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. AmJHumGenet. 1999, 65: 689-698.
13.
go back to reference Jones KB, Piombo V, Searby C, Kurriger G, Yang B, Grabellus F, Roughley PJ, Morcuende JA, Buckwalter JA, Capecchi MR, Vortkamp A, Sheffield VC: A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes. Proceedings of the National Academy of Sciences of the United States of America. 2010, 107 (5): 2054-2059. 10.1073/pnas.0910875107.CrossRefPubMedPubMedCentral Jones KB, Piombo V, Searby C, Kurriger G, Yang B, Grabellus F, Roughley PJ, Morcuende JA, Buckwalter JA, Capecchi MR, Vortkamp A, Sheffield VC: A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes. Proceedings of the National Academy of Sciences of the United States of America. 2010, 107 (5): 2054-2059. 10.1073/pnas.0910875107.CrossRefPubMedPubMedCentral
14.
go back to reference Jennes I, Pedrini E, Zuntini M, Mordenti M, Balkassmi S, Asteggiano CG, Casey B, Bakker B, Sangiorgi L, Wuyts W: Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb). Human mutation. 2009, 30 (12): 1620-1627. 10.1002/humu.21123.CrossRefPubMed Jennes I, Pedrini E, Zuntini M, Mordenti M, Balkassmi S, Asteggiano CG, Casey B, Bakker B, Sangiorgi L, Wuyts W: Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb). Human mutation. 2009, 30 (12): 1620-1627. 10.1002/humu.21123.CrossRefPubMed
15.
go back to reference White SJ, Vink GR, Kriek M, Wuyts W, Schouten J, Bakker B, Breuning MH, den Dunnen JT: Two-color multiplex ligation-dependent probe amplification: detecting genomic rearrangements in hereditary multiple exostoses. Human mutation. 2004, 24 (1): 86-92. 10.1002/humu.20054.CrossRefPubMed White SJ, Vink GR, Kriek M, Wuyts W, Schouten J, Bakker B, Breuning MH, den Dunnen JT: Two-color multiplex ligation-dependent probe amplification: detecting genomic rearrangements in hereditary multiple exostoses. Human mutation. 2004, 24 (1): 86-92. 10.1002/humu.20054.CrossRefPubMed
16.
go back to reference Jennes I, Entius MM, Van Hul E, Parra A, Sangiorgi L, Wuyts W: Mutation screening of EXT1 and EXT2 by denaturing high-performance liquid chromatography, direct sequencing analysis, fluorescence in situ hybridization, and a new multiplex ligation-dependent probe amplification probe set in patients with multiple osteochondromas. J Mol Diagn. 2008, 10 (1): 85-92. 10.2353/jmoldx.2008.070086.CrossRefPubMedPubMedCentral Jennes I, Entius MM, Van Hul E, Parra A, Sangiorgi L, Wuyts W: Mutation screening of EXT1 and EXT2 by denaturing high-performance liquid chromatography, direct sequencing analysis, fluorescence in situ hybridization, and a new multiplex ligation-dependent probe amplification probe set in patients with multiple osteochondromas. J Mol Diagn. 2008, 10 (1): 85-92. 10.2353/jmoldx.2008.070086.CrossRefPubMedPubMedCentral
17.
go back to reference Chen JM, Cooper DN, Ferec C, Kehrer-Sawatzki H, Patrinos GP: Genomic rearrangements in inherited disease and cancer. Seminars in cancer biology. 20 (4): 222-233. Chen JM, Cooper DN, Ferec C, Kehrer-Sawatzki H, Patrinos GP: Genomic rearrangements in inherited disease and cancer. Seminars in cancer biology. 20 (4): 222-233.
18.
go back to reference Hall BD, Langer LO, Giedion A, Smith DW, Cohen MM, Beals RK, Brandner M: Langer-Giedion syndrome. Birth defects original article series. 1974, 10 (12): 147-164.PubMed Hall BD, Langer LO, Giedion A, Smith DW, Cohen MM, Beals RK, Brandner M: Langer-Giedion syndrome. Birth defects original article series. 1974, 10 (12): 147-164.PubMed
19.
go back to reference Lüdecke HJ, Wagner MJ, Nardmann J, La Pillo B, Parrish JE, Willems PJ, Haan EA, Frydman M, Hamers GJH, Wells DE, Horsthemke B: Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer-Giedion syndrome. Human molecular genetics. 1995, 4 (1): 31-36. 10.1093/hmg/4.1.31.CrossRefPubMed Lüdecke HJ, Wagner MJ, Nardmann J, La Pillo B, Parrish JE, Willems PJ, Haan EA, Frydman M, Hamers GJH, Wells DE, Horsthemke B: Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer-Giedion syndrome. Human molecular genetics. 1995, 4 (1): 31-36. 10.1093/hmg/4.1.31.CrossRefPubMed
20.
go back to reference Bartsch O, Wuyts W, Van Hul W, Hecht JT, Meinecke P, Hogue D, Werner W, Zabel B, Hinkel GK, Powell CM, Shaffer LG, Willems PJ: Delineation of a contiguous gene syndrome with multiple exostoses, enlarged parietal foramina, craniofacial dysostosis and mental retardation, caused by deletions on the short arm of chromosome 11. American journal of human genetics. 1996, 58: 734-742.PubMedPubMedCentral Bartsch O, Wuyts W, Van Hul W, Hecht JT, Meinecke P, Hogue D, Werner W, Zabel B, Hinkel GK, Powell CM, Shaffer LG, Willems PJ: Delineation of a contiguous gene syndrome with multiple exostoses, enlarged parietal foramina, craniofacial dysostosis and mental retardation, caused by deletions on the short arm of chromosome 11. American journal of human genetics. 1996, 58: 734-742.PubMedPubMedCentral
21.
go back to reference Romeike BF, Wuyts W: Proximal chromosome 11p contiguous gene deletion syndrome phenotype: case report and review of the literature. Clinical neuropathology. 2007, 26 (1): 1-11.CrossRefPubMed Romeike BF, Wuyts W: Proximal chromosome 11p contiguous gene deletion syndrome phenotype: case report and review of the literature. Clinical neuropathology. 2007, 26 (1): 1-11.CrossRefPubMed
22.
go back to reference Szuhai K, Jennes I, de Jong D, Bovee JV, Wiweger M, Wuyts W, Hogendoorn PC: Tiling resolution array-CGH shows that somatic mosaic deletion of the EXT gene is causative in EXT gene mutation negative multiple osteochondromas patients. Human mutation. 32 (2): E2036-2049. Szuhai K, Jennes I, de Jong D, Bovee JV, Wiweger M, Wuyts W, Hogendoorn PC: Tiling resolution array-CGH shows that somatic mosaic deletion of the EXT gene is causative in EXT gene mutation negative multiple osteochondromas patients. Human mutation. 32 (2): E2036-2049.
23.
go back to reference Abeysinghe SS, Chuzhanova N, Krawczak M, Ball EV, Cooper DN: Translocation and gross deletion breakpoints in human inherited disease and cancer I: Nucleotide composition and recombination-associated motifs. Human mutation. 2003, 22 (3): 229-244. 10.1002/humu.10254.CrossRefPubMed Abeysinghe SS, Chuzhanova N, Krawczak M, Ball EV, Cooper DN: Translocation and gross deletion breakpoints in human inherited disease and cancer I: Nucleotide composition and recombination-associated motifs. Human mutation. 2003, 22 (3): 229-244. 10.1002/humu.10254.CrossRefPubMed
24.
go back to reference Lieber MR: The mechanism of human nonhomologous DNA end joining. The Journal of biological chemistry. 2008, 283 (1): 1-5.CrossRefPubMed Lieber MR: The mechanism of human nonhomologous DNA end joining. The Journal of biological chemistry. 2008, 283 (1): 1-5.CrossRefPubMed
25.
go back to reference Ma JL, Kim EM, Haber JE, Lee SE: Yeast Mre11 and Rad1 proteins define a Ku-independent mechanism to repair double-strand breaks lacking overlapping end sequences. Molecular and cellular biology. 2003, 23 (23): 8820-8828. 10.1128/MCB.23.23.8820-8828.2003.CrossRefPubMedPubMedCentral Ma JL, Kim EM, Haber JE, Lee SE: Yeast Mre11 and Rad1 proteins define a Ku-independent mechanism to repair double-strand breaks lacking overlapping end sequences. Molecular and cellular biology. 2003, 23 (23): 8820-8828. 10.1128/MCB.23.23.8820-8828.2003.CrossRefPubMedPubMedCentral
26.
go back to reference McVey M, Lee SE: MMEJ repair of double-strand breaks (director's cut): deleted sequences and alternative endings. Trends Genet. 2008, 24 (11): 529-538. 10.1016/j.tig.2008.08.007.CrossRefPubMed McVey M, Lee SE: MMEJ repair of double-strand breaks (director's cut): deleted sequences and alternative endings. Trends Genet. 2008, 24 (11): 529-538. 10.1016/j.tig.2008.08.007.CrossRefPubMed
27.
go back to reference Hastings PJ, Ira G, Lupski JR: A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS genetics. 2009, 5 (1): e1000327-10.1371/journal.pgen.1000327.CrossRefPubMedPubMedCentral Hastings PJ, Ira G, Lupski JR: A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS genetics. 2009, 5 (1): e1000327-10.1371/journal.pgen.1000327.CrossRefPubMedPubMedCentral
28.
go back to reference Zucman-Rossi J, Legoix P, Der Sarkissian H, Cheret G, Sor F, Bernardi A, Cazes L, Giraud S, Ollagnon E, Lenoir G, Thomas G: NF2 gene in neurofibromatosis type 2 patients. Human molecular genetics. 1998, 7 (13): 2095-2101. 10.1093/hmg/7.13.2095.CrossRefPubMed Zucman-Rossi J, Legoix P, Der Sarkissian H, Cheret G, Sor F, Bernardi A, Cazes L, Giraud S, Ollagnon E, Lenoir G, Thomas G: NF2 gene in neurofibromatosis type 2 patients. Human molecular genetics. 1998, 7 (13): 2095-2101. 10.1093/hmg/7.13.2095.CrossRefPubMed
29.
go back to reference van Zelm MC, Geertsema C, Nieuwenhuis N, de Ridder D, Conley ME, Schiff C, Tezcan I, Bernatowska E, Hartwig NG, Sanders EA, Litzman J, Kondratenko I, van Dongen JJ, van der Burg M: Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements. American journal of human genetics. 2008, 82 (2): 320-332. 10.1016/j.ajhg.2007.10.011.CrossRefPubMedPubMedCentral van Zelm MC, Geertsema C, Nieuwenhuis N, de Ridder D, Conley ME, Schiff C, Tezcan I, Bernatowska E, Hartwig NG, Sanders EA, Litzman J, Kondratenko I, van Dongen JJ, van der Burg M: Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements. American journal of human genetics. 2008, 82 (2): 320-332. 10.1016/j.ajhg.2007.10.011.CrossRefPubMedPubMedCentral
30.
go back to reference Deininger PL, Batzer MA: Alu repeats and human disease. Molecular genetics and metabolism. 1999, 67 (3): 183-193. 10.1006/mgme.1999.2864.CrossRefPubMed Deininger PL, Batzer MA: Alu repeats and human disease. Molecular genetics and metabolism. 1999, 67 (3): 183-193. 10.1006/mgme.1999.2864.CrossRefPubMed
32.
go back to reference Weiner AM, Deininger PL, Efstratiadis A: Nonviral retroposons: genes, pseudogenes, and transposable elements generated by the reverse flow of genetic information. Annual review of biochemistry. 1986, 55: 631-661. 10.1146/annurev.bi.55.070186.003215.CrossRefPubMed Weiner AM, Deininger PL, Efstratiadis A: Nonviral retroposons: genes, pseudogenes, and transposable elements generated by the reverse flow of genetic information. Annual review of biochemistry. 1986, 55: 631-661. 10.1146/annurev.bi.55.070186.003215.CrossRefPubMed
33.
go back to reference Hasler J, Samuelsson T, Strub K: Useful 'junk': Alu RNAs in the human transcriptome. Cell Mol Life Sci. 2007, 64 (14): 1793-1800. 10.1007/s00018-007-7084-0.CrossRefPubMed Hasler J, Samuelsson T, Strub K: Useful 'junk': Alu RNAs in the human transcriptome. Cell Mol Life Sci. 2007, 64 (14): 1793-1800. 10.1007/s00018-007-7084-0.CrossRefPubMed
34.
go back to reference Shaw CJ, Lupski JR: Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Human molecular genetics. 2004, 13 (Spec No 1): R57-64.CrossRefPubMed Shaw CJ, Lupski JR: Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Human molecular genetics. 2004, 13 (Spec No 1): R57-64.CrossRefPubMed
35.
go back to reference de Smith AJ, Tsalenko A, Sampas N, Scheffer A, Yamada NA, Tsang P, Ben-Dor A, Yakhini Z, Ellis RJ, Bruhn L, Laderman S, Froguel P, Blakemore AI: Array CGH analysis of copy number variation identifies 1284 new genes variant in healthy white males: implications for association studies of complex diseases. Human molecular genetics. 2007, 16 (23): 2783-2794. 10.1093/hmg/ddm208.CrossRefPubMed de Smith AJ, Tsalenko A, Sampas N, Scheffer A, Yamada NA, Tsang P, Ben-Dor A, Yakhini Z, Ellis RJ, Bruhn L, Laderman S, Froguel P, Blakemore AI: Array CGH analysis of copy number variation identifies 1284 new genes variant in healthy white males: implications for association studies of complex diseases. Human molecular genetics. 2007, 16 (23): 2783-2794. 10.1093/hmg/ddm208.CrossRefPubMed
36.
go back to reference Sen SK, Han K, Wang J, Lee J, Wang H, Callinan PA, Dyer M, Cordaux R, Liang P, Batzer MA: Human genomic deletions mediated by recombination between Alu elements. American journal of human genetics. 2006, 79 (1): 41-53. 10.1086/504600.CrossRefPubMedPubMedCentral Sen SK, Han K, Wang J, Lee J, Wang H, Callinan PA, Dyer M, Cordaux R, Liang P, Batzer MA: Human genomic deletions mediated by recombination between Alu elements. American journal of human genetics. 2006, 79 (1): 41-53. 10.1086/504600.CrossRefPubMedPubMedCentral
37.
go back to reference Han K, Lee J, Meyer TJ, Wang J, Sen SK, Srikanta D, Liang P, Batzer MA: Alu recombination-mediated structural deletions in the chimpanzee genome. PLoS genetics. 2007, 3 (10): 1939-1949.CrossRefPubMed Han K, Lee J, Meyer TJ, Wang J, Sen SK, Srikanta D, Liang P, Batzer MA: Alu recombination-mediated structural deletions in the chimpanzee genome. PLoS genetics. 2007, 3 (10): 1939-1949.CrossRefPubMed
38.
go back to reference Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann N, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M, Gibbs RA, Muzny DM, Scherer SE, Bouck JB, Sodergren EJ, Worley KC, Rives CM, Gorrell JH, Metzker ML, Naylor SL, Kucherlapati RS, Nelson DL, Weinstock GM, Sakaki Y, Fujiyama A, Hattori M, Yada T, Toyoda A, Itoh T, Kawagoe C, Watanabe H, Totoki Y, Taylor T, Weissenbach J, Heilig R, Saurin W, Artiguenave F, Brottier P, Bruls T, Pelletier E, Robert C, Wincker P, Smith DR, Doucette-Stamm L, Rubenfield M, Weinstock K, Lee HM, Dubois J, Rosenthal A, Platzer M, Nyakatura G, Taudien S, Rump A, Yang H, Yu J, Wang J, Huang G, Gu J, Hood L, Rowen L, Madan A, Qin S, Davis RW, Federspiel NA, Abola AP, Proctor MJ, Myers RM, Schmutz J, Dickson M, Grimwood J, Cox DR, Olson MV, Kaul R, Raymond C, Shimizu N, Kawasaki K, Minoshima S, Evans GA, Athanasiou M, Schultz R, Roe BA, Chen F, Pan H, Ramser J, Lehrach H, Reinhardt R, McCombie WR, de la Bastide M, Dedhia N, Blocker H, Hornischer K, Nordsiek G, Agarwala R, Aravind L, Bailey JA, Bateman A, Batzoglou S, Birney E, Bork P, Brown DG, Burge CB, Cerutti L, Chen HC, Church D, Clamp M, Copley RR, Doerks T, Eddy SR, Eichler EE, Furey TS, Galagan J, Gilbert JG, Harmon C, Hayashizaki Y, Haussler D, Hermjakob H, Hokamp K, Jang W, Johnson LS, Jones TA, Kasif S, Kaspryzk A, Kennedy S, Kent WJ, Kitts P, Koonin EV, Korf I, Kulp D, Lancet D, Lowe TM, McLysaght A, Mikkelsen T, Moran JV, Mulder N, Pollara VJ, Ponting CP, Schuler G, Schultz J, Slater G, Smit AF, Stupka E, Szustakowski J, Thierry-Mieg D, Thierry-Mieg J, Wagner L, Wallis J, Wheeler R, Williams A, Wolf YI, Wolfe KH, Yang SP, Yeh RF, Collins F, Guyer MS, Peterson J, Felsenfeld A, Wetterstrand KA, Patrinos A, Morgan MJ, de Jong P, Catanese JJ, Osoegawa K, Shizuya H, Choi S, Chen YJ: Initial sequencing and analysis of the human genome. Nature. 2001, 409 (6822): 860-921. 10.1038/35057062.CrossRefPubMed Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann N, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M, Gibbs RA, Muzny DM, Scherer SE, Bouck JB, Sodergren EJ, Worley KC, Rives CM, Gorrell JH, Metzker ML, Naylor SL, Kucherlapati RS, Nelson DL, Weinstock GM, Sakaki Y, Fujiyama A, Hattori M, Yada T, Toyoda A, Itoh T, Kawagoe C, Watanabe H, Totoki Y, Taylor T, Weissenbach J, Heilig R, Saurin W, Artiguenave F, Brottier P, Bruls T, Pelletier E, Robert C, Wincker P, Smith DR, Doucette-Stamm L, Rubenfield M, Weinstock K, Lee HM, Dubois J, Rosenthal A, Platzer M, Nyakatura G, Taudien S, Rump A, Yang H, Yu J, Wang J, Huang G, Gu J, Hood L, Rowen L, Madan A, Qin S, Davis RW, Federspiel NA, Abola AP, Proctor MJ, Myers RM, Schmutz J, Dickson M, Grimwood J, Cox DR, Olson MV, Kaul R, Raymond C, Shimizu N, Kawasaki K, Minoshima S, Evans GA, Athanasiou M, Schultz R, Roe BA, Chen F, Pan H, Ramser J, Lehrach H, Reinhardt R, McCombie WR, de la Bastide M, Dedhia N, Blocker H, Hornischer K, Nordsiek G, Agarwala R, Aravind L, Bailey JA, Bateman A, Batzoglou S, Birney E, Bork P, Brown DG, Burge CB, Cerutti L, Chen HC, Church D, Clamp M, Copley RR, Doerks T, Eddy SR, Eichler EE, Furey TS, Galagan J, Gilbert JG, Harmon C, Hayashizaki Y, Haussler D, Hermjakob H, Hokamp K, Jang W, Johnson LS, Jones TA, Kasif S, Kaspryzk A, Kennedy S, Kent WJ, Kitts P, Koonin EV, Korf I, Kulp D, Lancet D, Lowe TM, McLysaght A, Mikkelsen T, Moran JV, Mulder N, Pollara VJ, Ponting CP, Schuler G, Schultz J, Slater G, Smit AF, Stupka E, Szustakowski J, Thierry-Mieg D, Thierry-Mieg J, Wagner L, Wallis J, Wheeler R, Williams A, Wolf YI, Wolfe KH, Yang SP, Yeh RF, Collins F, Guyer MS, Peterson J, Felsenfeld A, Wetterstrand KA, Patrinos A, Morgan MJ, de Jong P, Catanese JJ, Osoegawa K, Shizuya H, Choi S, Chen YJ: Initial sequencing and analysis of the human genome. Nature. 2001, 409 (6822): 860-921. 10.1038/35057062.CrossRefPubMed
Metadata
Title
Breakpoint characterization of large deletions in EXT1 or EXT2 in 10 Multiple Osteochondromas families
Authors
Ivy Jennes
Danielle de Jong
Kirsten Mees
Pancras CW Hogendoorn
Karoly Szuhai
Wim Wuyts
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2011
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-12-85

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