Home LiteratureArticle Details
PMID: 10090893 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

American journal of human genetics ·Vol. 64 ·No. 4 ·1999-04-00 ·Pages 1076-86

Edelmann L, Pandita RK, Morrow BE

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.

MeSH Terms
Abnormalities, Multiple/genetics Base Sequence Chromosome Breakage/genetics Chromosome Deletion Chromosomes, Human, Pair 22/genetics DNA Fingerprinting DiGeorge Syndrome/genetics Female Genetic Markers/genetics Genetic Predisposition to Disease Haplotypes/genetics Humans In Situ Hybridization, Fluorescence Male Multigene Family/genetics Pedigree Physical Chromosome Mapping Pseudogenes/genetics Recombination, Genetic/genetics Repetitive Sequences, Nucleic Acid/genetics Sequence Homology, Nucleic Acid Syndrome
Chemicals
Genetic Markers
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Edelmann L
Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Pandita R K
Morrow B E
References (42)
42 references, click to expand
  1. 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):6303-7 PMID: 1676842
  2. Cat eye syndrome chromosome breakpoint clustering: identification of two intervals also associated with 22q11 deletion syndrome breakpoints.
    Cytogenet Cell Genet. 1998;81(3-4):222-8 PMID: 9730608
  3. 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):1207-18 PMID: 1746552
  4. Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus.
    Lancet. 1992 May 9;339(8802):1138-9 PMID: 1349369
  5. Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome.
    Am J Med Genet. 1992 Sep 15;44(2):261-8 PMID: 1360769
  6. 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 PMID: 1303282
  7. Low-copy-number repeat sequences flank the DiGeorge/velo-cardio-facial syndrome loci at 22q11.
    Hum Mol Genet. 1993 Feb;2(2):191-6 PMID: 8499906
  8. Molecular cytogenetic characterization of the DiGeorge syndrome region using fluorescence in situ hybridization.
    Genomics. 1993 Aug;17(2):403-7 PMID: 8406492
  9. Expression of multiple gamma-glutamyltransferase genes in man.
    Biochem J. 1994 Feb 1;297 ( Pt 3):503-8 PMID: 7906515
  10. A new bacteriophage P1-derived vector for the propagation of large human DNA fragments.
    Nat Genet. 1994 Jan;6(1):84-9 PMID: 8136839
  11. Two autosomal dominant neuropathies result from reciprocal DNA duplication/deletion of a region on chromosome 17.
    Hum Mol Genet. 1994 Feb;3(2):223-8 PMID: 8004087
  12. 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):4434-43 PMID: 7722300
  13. Molecular definition of the 22q11 deletions in velo-cardio-facial syndrome.
    Am J Hum Genet. 1995 Jun;56(6):1391-403 PMID: 7762562
  14. Cloning a balanced translocation associated with DiGeorge syndrome and identification of a disrupted candidate gene.
    Nat Genet. 1995 Jul;10(3):269-78 PMID: 7670464
  15. Velo-cardio-facial syndrome: frequency and extent of 22q11 deletions.
    Am J Med Genet. 1995 Jul 3;57(3):514-22 PMID: 7677167
  16. A high-density YAC contig map of human chromosome 22.
    Nature. 1995 Sep 28;377(6547 Suppl):367-79 PMID: 7566101
  17. A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element.
    Nat Genet. 1996 Mar;12(3):288-97 PMID: 8589720
  18. Formation of nuclear bodies in cells overexpressing the nuclear pore protein POM121.
    Exp Cell Res. 1996 May 25;225(1):75-84 PMID: 8635519
  19. The organization of the human immunoglobulin lambda gene locus.
    Genome Res. 1995 Sep;5(2):125-35 PMID: 9132267
  20. 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):328-36 PMID: 8812460
  21. Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams-Beuren syndrome.
    Hum Mol Genet. 1996 Dec;5(12):1893-8 PMID: 8968740
  22. The organization of the gamma-glutamyl transferase genes and other low copy repeats in human chromosome 22q11.
    Genome Res. 1997 May;7(5):522-31 PMID: 9149947
  23. Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.
    Am J Hum Genet. 1997 Sep;61(3):620-9 PMID: 9326327
  24. 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):747-58 PMID: 10053009
  25. 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 PMID: 272242
  26. 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):148-58 PMID: 6785205
  27. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia.
    Nature. 1982 Dec 23;300(5894):765-7 PMID: 6960256
  28. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia.
    Nature. 1985 Jun 13-19;315(6020):550-4 PMID: 2989692
  29. 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):1802-6 PMID: 3006074
  30. Interstitial deletion of (17)(p11.2p11.2) in nine patients.
    Am J Med Genet. 1986 Jul;24(3):393-414 PMID: 2425619
  31. DiGeorge syndrome and 22q11 rearrangements.
    Hum Genet. 1986 Oct;74(2):206 PMID: 3770751
  32. Duplication of the bcr and gamma-glutamyl transpeptidase genes.
    Nucleic Acids Res. 1988 Aug 25;16(16):8045-56 PMID: 2901712
  33. Linear order of the four BCR-related loci in 22q11.
    Genomics. 1988 Aug;3(2):168-71 PMID: 3267213
  34. Dependence of intrachromosomal recombination in mammalian cells on uninterrupted homology.
    Mol Cell Biol. 1988 Dec;8(12):5350-7 PMID: 2854196
  35. Chromosomal region of the cystic fibrosis gene in yeast artificial chromosomes: a model for human genome mapping.
    Science. 1990 Oct 5;250(4977):94-8 PMID: 2218515
  36. Sex-dependent rearrangements resulting in CMT1A and HNPP.
    Nat Genet. 1997 Oct;17(2):136-7 PMID: 9326925
  37. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome.
    Nat Genet. 1997 Oct;17(2):154-63 PMID: 9326934
  38. 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):325-34 PMID: 9466987
  39. Molecular cytogenetic evidence for a common breakpoint in the largest inverted duplications of chromosome 15.
    Am J Hum Genet. 1998 Apr;62(4):925-36 PMID: 9529335
  40. High level of unequal meiotic crossovers at the origin of the 22q11. 2 and 7q11.23 deletions.
    Hum Mol Genet. 1998 May;7(5):887-94 PMID: 9536094
  41. 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):1023-33 PMID: 9545397
  42. DNA duplication associated with Charcot-Marie-Tooth disease type 1A.
    Cell. 1991 Jul 26;66(2):219-32 PMID: 1677316
Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/302343
Published
1999-04-00
Pages
1076-86
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1377832
Subset
IM
Grants
NICHD NIH HHS · P0-1 HD 34980-01 · United States
NCI NIH HHS · T32 CA09060 · United States
External Links
PubMed source DOI: 10.1086/302343 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2