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. 1999 Apr;64(4):1076–1086. doi: 10.1086/302343

Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome.

L Edelmann 1, R K Pandita 1, B E Morrow 1
PMCID: PMC1377832  PMID: 10090893

Abstract

Velo-cardio-facial syndrome (VCFS) is the most common microdeletion syndrome in humans. It occurs with an estimated frequency of 1 in 4, 000 live births. Most cases occur sporadically, indicating that the deletion is recurrent in the population. More than 90% of patients with VCFS and a 22q11 deletion have a similar 3-Mb hemizygous deletion, suggesting that sequences at the breakpoints confer susceptibility to rearrangements. To define the region containing the chromosome breakpoints, we constructed an 8-kb-resolution physical map. We identified a low-copy repeat in the vicinity of both breakpoints. A set of genetic markers were integrated into the physical map to determine whether the deletions occur within the repeat. Haplotype analysis with genetic markers that flank the repeats showed that most patients with VCFS had deletion breakpoints in the repeat. Within the repeat is a 200-kb duplication of sequences, including a tandem repeat of genes/pseudogenes, surrounding the breakpoints. The genes in the repeat are GGT, BCRL, V7-rel, POM121-like, and GGT-rel. Physical mapping and genomic fingerprint analysis showed that the repeats are virtually identical in the 200-kb region, suggesting that the deletion is mediated by homologous recombination. Examination of two three-generation families showed that meiotic intrachromosomal recombination mediated the deletion.

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Selected References

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  1. Augusseau S., Jouk S., Jalbert P., Prieur M. DiGeorge syndrome and 22q11 rearrangements. Hum Genet. 1986 Oct;74(2):206–206. doi: 10.1007/BF00282098. [DOI] [PubMed] [Google Scholar]
  2. Baumer A., Dutly F., Balmer D., Riegel M., Tükel T., Krajewska-Walasek M., Schinzel A. A. High level of unequal meiotic crossovers at the origin of the 22q11. 2 and 7q11.23 deletions. Hum Mol Genet. 1998 May;7(5):887–894. doi: 10.1093/hmg/7.5.887. [DOI] [PubMed] [Google Scholar]
  3. Budarf M. L., Collins J., Gong W., Roe B., Wang Z., Bailey L. C., Sellinger B., Michaud D., Driscoll D. A., Emanuel B. S. Cloning a balanced translocation associated with DiGeorge syndrome and identification of a disrupted candidate gene. Nat Genet. 1995 Jul;10(3):269–278. doi: 10.1038/ng0795-269. [DOI] [PubMed] [Google Scholar]
  4. Budarf M., Canaani E., Emanuel B. S. Linear order of the four BCR-related loci in 22q11. Genomics. 1988 Aug;3(2):168–171. doi: 10.1016/0888-7543(88)90149-8. [DOI] [PubMed] [Google Scholar]
  5. Carlson C., Sirotkin H., Pandita R., Goldberg R., McKie J., Wadey R., Patanjali S. R., Weissman S. M., Anyane-Yeboa K., Warburton D. Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. Am J Hum Genet. 1997 Sep;61(3):620–629. doi: 10.1086/515508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chance P. F., Abbas N., Lensch M. W., Pentao L., Roa B. B., Patel P. I., Lupski J. R. Two autosomal dominant neuropathies result from reciprocal DNA duplication/deletion of a region on chromosome 17. Hum Mol Genet. 1994 Feb;3(2):223–228. doi: 10.1093/hmg/3.2.223. [DOI] [PubMed] [Google Scholar]
  7. Chen K. S., Manian P., Koeuth T., Potocki L., Zhao Q., Chinault A. C., Lee C. C., Lupski J. R. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nat Genet. 1997 Oct;17(2):154–163. doi: 10.1038/ng1097-154. [DOI] [PubMed] [Google Scholar]
  8. Collins J. E., Cole C. G., Smink L. J., Garrett C. L., Leversha M. A., Soderlund C. A., Maslen G. L., Everett L. A., Rice K. M., Coffey A. J. A high-density YAC contig map of human chromosome 22. Nature. 1995 Sep 28;377(6547 Suppl):367–379. doi: 10.1038/377367a0. [DOI] [PubMed] [Google Scholar]
  9. Collins J. E., Mungall A. J., Badcock K. L., Fay J. M., Dunham I. The organization of the gamma-glutamyl transferase genes and other low copy repeats in human chromosome 22q11. Genome Res. 1997 May;7(5):522–531. doi: 10.1101/gr.7.5.522. [DOI] [PubMed] [Google Scholar]
  10. Courtay C., Heisterkamp N., Siest G., Groffen J. Expression of multiple gamma-glutamyltransferase genes in man. Biochem J. 1994 Feb 1;297(Pt 3):503–508. doi: 10.1042/bj2970503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Driscoll D. A., Spinner N. B., Budarf M. L., McDonald-McGinn D. M., Zackai E. H., Goldberg R. B., Shprintzen R. J., Saal H. M., Zonana J., Jones M. C. Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet. 1992 Sep 15;44(2):261–268. doi: 10.1002/ajmg.1320440237. [DOI] [PubMed] [Google Scholar]
  12. Dutly F., Schinzel A. Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams-Beuren syndrome. Hum Mol Genet. 1996 Dec;5(12):1893–1898. doi: 10.1093/hmg/5.12.1893. [DOI] [PubMed] [Google Scholar]
  13. Funke B., Edelmann L., McCain N., Pandita R. K., Ferreira J., Merscher S., Zohouri M., Cannizzaro L., Shanske A., Morrow B. E. Der(22) syndrome and velo-cardio-facial syndrome/DiGeorge syndrome share a 1.5-Mb region of overlap on chromosome 22q11. Am J Hum Genet. 1999 Mar;64(3):747–758. doi: 10.1086/302284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Green E. D., Olson M. V. Chromosomal region of the cystic fibrosis gene in yeast artificial chromosomes: a model for human genome mapping. Science. 1990 Oct 5;250(4977):94–98. doi: 10.1126/science.2218515. [DOI] [PubMed] [Google Scholar]
  15. Greenberg F., Guzzetta V., Montes de Oca-Luna R., Magenis R. E., Smith A. C., Richter S. F., Kondo I., Dobyns W. B., Patel P. I., Lupski J. R. Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2). Am J Hum Genet. 1991 Dec;49(6):1207–1218. [PMC free article] [PubMed] [Google Scholar]
  16. Halford S., Lindsay E., Nayudu M., Carey A. H., Baldini A., Scambler P. J. Low-copy-number repeat sequences flank the DiGeorge/velo-cardio-facial syndrome loci at 22q11. Hum Mol Genet. 1993 Feb;2(2):191–196. doi: 10.1093/hmg/2.2.191. [DOI] [PubMed] [Google Scholar]
  17. Heisterkamp N., Groffen J. Duplication of the bcr and gamma-glutamyl transpeptidase genes. Nucleic Acids Res. 1988 Aug 25;16(16):8045–8056. doi: 10.1093/nar/16.16.8045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Heisterkamp N., Rajpert-De Meyts E., Uribe L., Forman H. J., Groffen J. Identification of a human gamma-glutamyl cleaving enzyme related to, but distinct from, gamma-glutamyl transpeptidase. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6303–6307. doi: 10.1073/pnas.88.14.6303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ioannou P. A., Amemiya C. T., Garnes J., Kroisel P. M., Shizuya H., Chen C., Batzer M. A., de Jong P. J. A new bacteriophage P1-derived vector for the propagation of large human DNA fragments. Nat Genet. 1994 Jan;6(1):84–89. doi: 10.1038/ng0194-84. [DOI] [PubMed] [Google Scholar]
  20. Kawasaki K., Minoshima S., Schooler K., Kudoh J., Asakawa S., de Jong P. J., Shimizu N. The organization of the human immunoglobulin lambda gene locus. Genome Res. 1995 Sep;5(2):125–135. doi: 10.1101/gr.5.2.125. [DOI] [PubMed] [Google Scholar]
  21. Lindsay E. A., Goldberg R., Jurecic V., Morrow B., Carlson C., Kucherlapati R. S., Shprintzen R. J., Baldini A. Velo-cardio-facial syndrome: frequency and extent of 22q11 deletions. Am J Med Genet. 1995 Jul 3;57(3):514–522. doi: 10.1002/ajmg.1320570339. [DOI] [PubMed] [Google Scholar]
  22. Lindsay E. A., Halford S., Wadey R., Scambler P. J., Baldini A. Molecular cytogenetic characterization of the DiGeorge syndrome region using fluorescence in situ hybridization. Genomics. 1993 Aug;17(2):403–407. doi: 10.1006/geno.1993.1339. [DOI] [PubMed] [Google Scholar]
  23. Liskay R. M., Stachelek J. L. Information transfer between duplicated chromosomal sequences in mammalian cells involves contiguous regions of DNA. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1802–1806. doi: 10.1073/pnas.83.6.1802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lopes J., Vandenberghe A., Tardieu S., Ionasescu V., Lévy N., Wood N., Tachi N., Bouche P., Latour P., Brice A. Sex-dependent rearrangements resulting in CMT1A and HNPP. Nat Genet. 1997 Oct;17(2):136–137. doi: 10.1038/ng1097-136. [DOI] [PubMed] [Google Scholar]
  25. Lupski J. R., de Oca-Luna R. M., Slaugenhaupt S., Pentao L., Guzzetta V., Trask B. J., Saucedo-Cardenas O., Barker D. F., Killian J. M., Garcia C. A. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell. 1991 Jul 26;66(2):219–232. doi: 10.1016/0092-8674(91)90613-4. [DOI] [PubMed] [Google Scholar]
  26. McTaggart K. E., Budarf M. L., Driscoll D. A., Emanuel B. S., Ferreira P., McDermid H. E. Cat eye syndrome chromosome breakpoint clustering: identification of two intervals also associated with 22q11 deletion syndrome breakpoints. Cytogenet Cell Genet. 1998;81(3-4):222–228. doi: 10.1159/000015035. [DOI] [PubMed] [Google Scholar]
  27. Morrow B., Goldberg R., Carlson C., Das Gupta R., Sirotkin H., Collins J., Dunham I., O'Donnell H., Scambler P., Shprintzen R. Molecular definition of the 22q11 deletions in velo-cardio-facial syndrome. Am J Hum Genet. 1995 Jun;56(6):1391–1403. [PMC free article] [PubMed] [Google Scholar]
  28. Osborne L. R., Martindale D., Scherer S. W., Shi X. M., Huizenga J., Heng H. H., Costa T., Pober B., Lew L., Brinkman J. Identification of genes from a 500-kb region at 7q11.23 that is commonly deleted in Williams syndrome patients. Genomics. 1996 Sep 1;36(2):328–336. doi: 10.1006/geno.1996.0469. [DOI] [PubMed] [Google Scholar]
  29. Pentao L., Wise C. A., Chinault A. C., Patel P. I., Lupski J. R. Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nat Genet. 1992 Dec;2(4):292–300. doi: 10.1038/ng1292-292. [DOI] [PubMed] [Google Scholar]
  30. Pérez Jurado L. A., Wang Y. K., Peoples R., Coloma A., Cruces J., Francke U. A duplicated gene in the breakpoint regions of the 7q11.23 Williams-Beuren syndrome deletion encodes the initiator binding protein TFII-I and BAP-135, a phosphorylation target of BTK. Hum Mol Genet. 1998 Mar;7(3):325–334. doi: 10.1093/hmg/7.3.325. [DOI] [PubMed] [Google Scholar]
  31. Reiter L. T., Hastings P. J., Nelis E., De Jonghe P., Van Broeckhoven C., Lupski J. R. Human meiotic recombination products revealed by sequencing a hotspot for homologous strand exchange in multiple HNPP deletion patients. Am J Hum Genet. 1998 May;62(5):1023–1033. doi: 10.1086/301827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Reiter L. T., Murakami T., Koeuth T., Pentao L., Muzny D. M., Gibbs R. A., Lupski J. R. A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element. Nat Genet. 1996 Mar;12(3):288–297. doi: 10.1038/ng0396-288. [DOI] [PubMed] [Google Scholar]
  33. Ruegg C. L., Rivas A., Madani N. D., Zeitung J., Laus R., Engleman E. G. V7, a novel leukocyte surface protein that participates in T cell activation. II. Molecular cloning and characterization of the V7 gene. J Immunol. 1995 May 1;154(9):4434–4443. [PubMed] [Google Scholar]
  34. Scambler P. J., Kelly D., Lindsay E., Williamson R., Goldberg R., Shprintzen R., Wilson D. I., Goodship J. A., Cross I. E., Burn J. Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet. 1992 May 9;339(8802):1138–1139. doi: 10.1016/0140-6736(92)90734-k. [DOI] [PubMed] [Google Scholar]
  35. Schinzel A., Schmid W., Fraccaro M., Tiepolo L., Zuffardi O., Opitz J. M., Lindsten J., Zetterqvist P., Enell H., Baccichetti C. The "cat eye syndrome": dicentric small marker chromosome probably derived from a no.22 (tetrasomy 22pter to q11) associated with a characteristic phenotype. Report of 11 patients and delineation of the clinical picture. Hum Genet. 1981;57(2):148–158. doi: 10.1007/BF00282012. [DOI] [PubMed] [Google Scholar]
  36. Shprintzen R. J., Goldberg R. B., Lewin M. L., Sidoti E. J., Berkman M. D., Argamaso R. V., Young D. A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome. Cleft Palate J. 1978 Jan;15(1):56–62. [PubMed] [Google Scholar]
  37. Shtivelman E., Lifshitz B., Gale R. P., Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985 Jun 13;315(6020):550–554. doi: 10.1038/315550a0. [DOI] [PubMed] [Google Scholar]
  38. Smith A. C., McGavran L., Robinson J., Waldstein G., Macfarlane J., Zonona J., Reiss J., Lahr M., Allen L., Magenis E. Interstitial deletion of (17)(p11.2p11.2) in nine patients. Am J Med Genet. 1986 Jul;24(3):393–414. doi: 10.1002/ajmg.1320240303. [DOI] [PubMed] [Google Scholar]
  39. Söderqvist H., Jiang W. Q., Ringertz N., Hallberg E. Formation of nuclear bodies in cells overexpressing the nuclear pore protein POM121. Exp Cell Res. 1996 May 25;225(1):75–84. doi: 10.1006/excr.1996.0158. [DOI] [PubMed] [Google Scholar]
  40. Waldman A. S., Liskay R. M. Dependence of intrachromosomal recombination in mammalian cells on uninterrupted homology. Mol Cell Biol. 1988 Dec;8(12):5350–5357. doi: 10.1128/mcb.8.12.5350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wandstrat A. E., Leana-Cox J., Jenkins L., Schwartz S. Molecular cytogenetic evidence for a common breakpoint in the largest inverted duplications of chromosome 15. Am J Hum Genet. 1998 Apr;62(4):925–936. doi: 10.1086/301777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. de Klein A., van Kessel A. G., Grosveld G., Bartram C. R., Hagemeijer A., Bootsma D., Spurr N. K., Heisterkamp N., Groffen J., Stephenson J. R. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1982 Dec 23;300(5894):765–767. doi: 10.1038/300765a0. [DOI] [PubMed] [Google Scholar]

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