Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome

Genomic organization and deletion endpoint analysis

Tamim H. Shaikh, Hiroki Kurahashi, Sulagna C. Saitta, Anna Mizrahy O'Hare, Ping Hu, Bruce A. Roe, Deborah A. Driscoll, Donna M. McDonald-McGinn, Elaine H. Zackai, Marcia L. Budarf, Beverly S. Emanuel

Research output: Contribution to journal › Article

371 Citations (Scopus)

Abstract

The 22q11.2 deletion syndrome, which includes DiGeorge and velocardiofacial syndromes (DGS/VCFS), is the most common microdeletion syndrome. The majority of deleted patients share a common 3 Mb hemizygous deletion of 22q11.2. The remaining patients include those who have smaller deletions that are nested within the 3 Mb typically deleted region (TDR) and a few with rare deletions that have no overlap with the TDR. The identification of chromosome 22-specific duplicated sequences or low copy repeats (LCRs) near the end-points of the 3 Mb TDR has led to the hypothesis that they mediate deletions of 22q11.2. The entire 3 Mb TDR has been sequenced, permitting detailed investigation of the LCRs and their involvement in the 22q11.2 deletions. Sequence analysis has identified four LCRs within the 3 Mb TDR. Although the LCRs differ in content and organization of shared modules, those modules that are common between them share 97-98% sequence identity with one another. By fluorescence in situ hybridization (FISH) analysis, the end-points of four variant 22q11.2 deletions appear to localize to the LCRs. Pulsed-field gel electrophoresis and Southern hybridization have been used to identify rearranged junction fragments from three variant deletions. Analysis of junction fragments by PCR and sequencing of the PCR products implicate the LCRs directly in the formation of 22q11.2 deletions. The evolutionary origin of the duplications on chromosome 22 has been assessed by FISH analysis of non-human primates. Multiple signals in Old World monkeys suggest that the duplication events may have occurred at least 20-25 million years ago.

Original languageEnglish
Pages (from-to)489-501
Number of pages13
JournalHuman Molecular Genetics
Volume9
Issue number4
Publication statusPublished - 01-03-2000
Externally publishedYes

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Genomic Segmental Duplications
DiGeorge Syndrome
Chromosomes, Human, Pair 22
Fluorescence In Situ Hybridization
Cercopithecidae
Polymerase Chain Reaction
Pulsed Field Gel Electrophoresis
Primates
Sequence Analysis

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Shaikh, T. H., Kurahashi, H., Saitta, S. C., O'Hare, A. M., Hu, P., Roe, B. A., ... Emanuel, B. S. (2000). Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: Genomic organization and deletion endpoint analysis. Human Molecular Genetics, 9(4), 489-501.
Shaikh, Tamim H. ; Kurahashi, Hiroki ; Saitta, Sulagna C. ; O'Hare, Anna Mizrahy ; Hu, Ping ; Roe, Bruce A. ; Driscoll, Deborah A. ; McDonald-McGinn, Donna M. ; Zackai, Elaine H. ; Budarf, Marcia L. ; Emanuel, Beverly S. / Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome : Genomic organization and deletion endpoint analysis. In: Human Molecular Genetics. 2000 ; Vol. 9, No. 4. pp. 489-501.
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abstract = "The 22q11.2 deletion syndrome, which includes DiGeorge and velocardiofacial syndromes (DGS/VCFS), is the most common microdeletion syndrome. The majority of deleted patients share a common 3 Mb hemizygous deletion of 22q11.2. The remaining patients include those who have smaller deletions that are nested within the 3 Mb typically deleted region (TDR) and a few with rare deletions that have no overlap with the TDR. The identification of chromosome 22-specific duplicated sequences or low copy repeats (LCRs) near the end-points of the 3 Mb TDR has led to the hypothesis that they mediate deletions of 22q11.2. The entire 3 Mb TDR has been sequenced, permitting detailed investigation of the LCRs and their involvement in the 22q11.2 deletions. Sequence analysis has identified four LCRs within the 3 Mb TDR. Although the LCRs differ in content and organization of shared modules, those modules that are common between them share 97-98{\%} sequence identity with one another. By fluorescence in situ hybridization (FISH) analysis, the end-points of four variant 22q11.2 deletions appear to localize to the LCRs. Pulsed-field gel electrophoresis and Southern hybridization have been used to identify rearranged junction fragments from three variant deletions. Analysis of junction fragments by PCR and sequencing of the PCR products implicate the LCRs directly in the formation of 22q11.2 deletions. The evolutionary origin of the duplications on chromosome 22 has been assessed by FISH analysis of non-human primates. Multiple signals in Old World monkeys suggest that the duplication events may have occurred at least 20-25 million years ago.",
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Shaikh, TH, Kurahashi, H, Saitta, SC, O'Hare, AM, Hu, P, Roe, BA, Driscoll, DA, McDonald-McGinn, DM, Zackai, EH, Budarf, ML & Emanuel, BS 2000, 'Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: Genomic organization and deletion endpoint analysis', Human Molecular Genetics, vol. 9, no. 4, pp. 489-501.

Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome : Genomic organization and deletion endpoint analysis. / Shaikh, Tamim H.; Kurahashi, Hiroki; Saitta, Sulagna C.; O'Hare, Anna Mizrahy; Hu, Ping; Roe, Bruce A.; Driscoll, Deborah A.; McDonald-McGinn, Donna M.; Zackai, Elaine H.; Budarf, Marcia L.; Emanuel, Beverly S.

In: Human Molecular Genetics, Vol. 9, No. 4, 01.03.2000, p. 489-501.

Research output: Contribution to journal › Article

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T1 - Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome

T2 - Genomic organization and deletion endpoint analysis

AU - Shaikh, Tamim H.

AU - Kurahashi, Hiroki

AU - Saitta, Sulagna C.

AU - O'Hare, Anna Mizrahy

AU - Hu, Ping

AU - Roe, Bruce A.

AU - Driscoll, Deborah A.

AU - McDonald-McGinn, Donna M.

AU - Zackai, Elaine H.

AU - Budarf, Marcia L.

AU - Emanuel, Beverly S.

PY - 2000/3/1

Y1 - 2000/3/1

N2 - The 22q11.2 deletion syndrome, which includes DiGeorge and velocardiofacial syndromes (DGS/VCFS), is the most common microdeletion syndrome. The majority of deleted patients share a common 3 Mb hemizygous deletion of 22q11.2. The remaining patients include those who have smaller deletions that are nested within the 3 Mb typically deleted region (TDR) and a few with rare deletions that have no overlap with the TDR. The identification of chromosome 22-specific duplicated sequences or low copy repeats (LCRs) near the end-points of the 3 Mb TDR has led to the hypothesis that they mediate deletions of 22q11.2. The entire 3 Mb TDR has been sequenced, permitting detailed investigation of the LCRs and their involvement in the 22q11.2 deletions. Sequence analysis has identified four LCRs within the 3 Mb TDR. Although the LCRs differ in content and organization of shared modules, those modules that are common between them share 97-98% sequence identity with one another. By fluorescence in situ hybridization (FISH) analysis, the end-points of four variant 22q11.2 deletions appear to localize to the LCRs. Pulsed-field gel electrophoresis and Southern hybridization have been used to identify rearranged junction fragments from three variant deletions. Analysis of junction fragments by PCR and sequencing of the PCR products implicate the LCRs directly in the formation of 22q11.2 deletions. The evolutionary origin of the duplications on chromosome 22 has been assessed by FISH analysis of non-human primates. Multiple signals in Old World monkeys suggest that the duplication events may have occurred at least 20-25 million years ago.

AB - The 22q11.2 deletion syndrome, which includes DiGeorge and velocardiofacial syndromes (DGS/VCFS), is the most common microdeletion syndrome. The majority of deleted patients share a common 3 Mb hemizygous deletion of 22q11.2. The remaining patients include those who have smaller deletions that are nested within the 3 Mb typically deleted region (TDR) and a few with rare deletions that have no overlap with the TDR. The identification of chromosome 22-specific duplicated sequences or low copy repeats (LCRs) near the end-points of the 3 Mb TDR has led to the hypothesis that they mediate deletions of 22q11.2. The entire 3 Mb TDR has been sequenced, permitting detailed investigation of the LCRs and their involvement in the 22q11.2 deletions. Sequence analysis has identified four LCRs within the 3 Mb TDR. Although the LCRs differ in content and organization of shared modules, those modules that are common between them share 97-98% sequence identity with one another. By fluorescence in situ hybridization (FISH) analysis, the end-points of four variant 22q11.2 deletions appear to localize to the LCRs. Pulsed-field gel electrophoresis and Southern hybridization have been used to identify rearranged junction fragments from three variant deletions. Analysis of junction fragments by PCR and sequencing of the PCR products implicate the LCRs directly in the formation of 22q11.2 deletions. The evolutionary origin of the duplications on chromosome 22 has been assessed by FISH analysis of non-human primates. Multiple signals in Old World monkeys suggest that the duplication events may have occurred at least 20-25 million years ago.

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Shaikh TH, Kurahashi H, Saitta SC, O'Hare AM, Hu P, Roe BA et al. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: Genomic organization and deletion endpoint analysis. Human Molecular Genetics. 2000 Mar 1;9(4):489-501.

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