TY - JOUR
T1 - A common molecular basis for rearrangement disorders on chromosome 22q11
AU - Edelmann, Lisa
AU - Pandita, Raj K.
AU - Spiteri, Elizabeth
AU - Funke, Birgit
AU - Goldberg, Rosalie
AU - Palanisamy, Nallasivam
AU - Chaganti, R. S.K.
AU - Magenis, Ellen
AU - Shprintzen, Robert J.
AU - Morrow, Bernice E.
N1 - Funding Information:
We thank Drs Raju Kucherlapati, Arthur Skoultchi, Anne Puech, Bruno Saint-Jore and Steven Somlo for their helpful suggestions. We thank the families for their participation in the study. B.E.M. is supported by NIH grant PO-1 HD34980-02, American Heart Association Grant-in-Aid, and Investigator-ship and March of Dimes Grant (FY98-0414). L.E. is supported by NIH grant T32 CA09060. B.F. is supported by a grant from Deutsche Forschungsgemeinschaft. R.J.S. is supported by NIH grant PO-1 HD34980-02.
PY - 1999
Y1 - 1999
N2 - The chromosome 22q11 region is susceptible to rearrangements that are associated with congenital anomaly disorders and malignant tumors. Three congenital anomaly disorders, cat-eye syndrome, der(22) syndrome and velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) are associated with tetrasomy, trisomy or monosomy, respectively, for part of chromosome 22q11. VCFS/DGS is the most common syndrome associated with 22q11 rearrangements. In order to determine whether there are particular regions on 22q11 that are prone to rearrangements, the deletion end-points in a large number of VCFS/DGS patients were defined by haplotype analysis. Most VCFS/DGS patients have a similar 3 Mb deletion, some have a nested distal deletion breakpoint resulting in a 1.5 Mb deletion and a few rare patients have unique deletions or translocations. The high prevalence of the disorder in the population and the fact that most cases occur sporadically suggest that sequences at or near the breakpoints confer susceptibility to chromosome rearrangements. To investigate this hypothesis, we developed hamster-human somatic hybrid cell lines from VCFS/DGS patients with all three classes of deletions and we now show that the breakpoints occur within similar low copy repeats, termed LCR22s. To support this idea further, we identified a family that carries an interstitial duplication of the same 3 Mb region that is deleted in VCFS/DGS patients. We present models to explain how the LCR22s can mediate different homologous recombination events, thereby generating a number of rearrangements that are associated with congenital anomaly disorders. We identified five additional copies of the LCR22 on 22q11 that may mediate other rearrangements leading to disease.
AB - The chromosome 22q11 region is susceptible to rearrangements that are associated with congenital anomaly disorders and malignant tumors. Three congenital anomaly disorders, cat-eye syndrome, der(22) syndrome and velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) are associated with tetrasomy, trisomy or monosomy, respectively, for part of chromosome 22q11. VCFS/DGS is the most common syndrome associated with 22q11 rearrangements. In order to determine whether there are particular regions on 22q11 that are prone to rearrangements, the deletion end-points in a large number of VCFS/DGS patients were defined by haplotype analysis. Most VCFS/DGS patients have a similar 3 Mb deletion, some have a nested distal deletion breakpoint resulting in a 1.5 Mb deletion and a few rare patients have unique deletions or translocations. The high prevalence of the disorder in the population and the fact that most cases occur sporadically suggest that sequences at or near the breakpoints confer susceptibility to chromosome rearrangements. To investigate this hypothesis, we developed hamster-human somatic hybrid cell lines from VCFS/DGS patients with all three classes of deletions and we now show that the breakpoints occur within similar low copy repeats, termed LCR22s. To support this idea further, we identified a family that carries an interstitial duplication of the same 3 Mb region that is deleted in VCFS/DGS patients. We present models to explain how the LCR22s can mediate different homologous recombination events, thereby generating a number of rearrangements that are associated with congenital anomaly disorders. We identified five additional copies of the LCR22 on 22q11 that may mediate other rearrangements leading to disease.
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U2 - 10.1093/hmg/8.7.1157
DO - 10.1093/hmg/8.7.1157
M3 - Article
C2 - 10369860
AN - SCOPUS:0032790898
SN - 0964-6906
VL - 8
SP - 1157
EP - 1167
JO - Human molecular genetics
JF - Human molecular genetics
IS - 7
ER -