TY - JOUR
T1 - Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients
AU - Carlson, C.
AU - Sirotkin, H.
AU - Pandita, R.
AU - Goldberg, R.
AU - McKie, J.
AU - Wadey, R.
AU - Patanjali, S. R.
AU - Weissman, S. M.
AU - Anyane-Yeboa, K.
AU - Warburton, D.
AU - Scambler, P.
AU - Shprintzen, R.
AU - Kucherlapati, R.
AU - Morrow, B. E.
N1 - Funding Information:
We are grateful to the patients and families who participated in the study. We thank Drs. A. Shanske, B. Gelb. W. V. Hul, and F. Beemer, as well as other clinicians, for identifying VCFS patients and obtaining blood samples from each patient and his or her relatives and for providing them for this study. Dr. C. Meijers kindly provided us with some of the cosmid addresses that were helpful for construction of the physical map. We are grateful for the gift of the hamster fibroblast cell line CHTG49 from Dr. Cynthia Jackson (Brown University). We thank Drs. A. Skoultchi, A. Puech, and B. Saint-Jore for their constant support. This work was supported by the Albert Einstein College of Medicine Human Genetics Program. B.E.M. is supported by NIH PO-1, HD 34980-01, a National Alliance for Research on Schizophrenia and Depression award, an American Heart Association Grant-in-Aid and Investiga-torship, and MOD Basil O’Conner Starter Scholar Research Award 5-FY95-0115.
PY - 1997/9
Y1 - 1997/9
N2 - Velo-cardio-facial syndrome (VCFS) is a relatively common developmental disorder characterized by craniofacial anomalies and conotruncal heart defects. Many VCFS patients have hemizygous deletions for a part of 22q11, suggesting that haploinsufficiency in this region is responsible for its etiology. Because most cases of VCFS are sporadic, portions of 22q11 may be prone to rearrangement. To understand the molecular basis for chromosomal deletions, we defined the extent of the deletion, by genotyping 151 VCFS patients and performing haplotype analysis on 105, using 15 consecutive polymorphic markers in 22q11. We found that 83% had a deletion and >90% of these had a similar ~3 Mb deletion, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement. We found no correlation between the presence or size of the deletion and the phenotype. To further define the chromosomal breakpoints among the VCFS patients, we developed somatic hybrid cell lines from a set of VCFS patients. An 11-kb resolution physical map of a 1,080-kb region that includes deletion breakpoints was constructed, incorporating genes and expressed sequence tags (ESTs) isolated by the hybridization selection method. The ordered markers were used to examine the two separated copies of chromosome 22 in the somatic hybrid cell lines. In some cases, we were able to map the chromosome breakpoints within a single cosmid. A 480-kb critical region for VCFS has been delineated, including the genes for GSCL, CTP, CLTD, HIRA, and TMVCF, as well as a number of novel ordered ESTs.
AB - Velo-cardio-facial syndrome (VCFS) is a relatively common developmental disorder characterized by craniofacial anomalies and conotruncal heart defects. Many VCFS patients have hemizygous deletions for a part of 22q11, suggesting that haploinsufficiency in this region is responsible for its etiology. Because most cases of VCFS are sporadic, portions of 22q11 may be prone to rearrangement. To understand the molecular basis for chromosomal deletions, we defined the extent of the deletion, by genotyping 151 VCFS patients and performing haplotype analysis on 105, using 15 consecutive polymorphic markers in 22q11. We found that 83% had a deletion and >90% of these had a similar ~3 Mb deletion, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement. We found no correlation between the presence or size of the deletion and the phenotype. To further define the chromosomal breakpoints among the VCFS patients, we developed somatic hybrid cell lines from a set of VCFS patients. An 11-kb resolution physical map of a 1,080-kb region that includes deletion breakpoints was constructed, incorporating genes and expressed sequence tags (ESTs) isolated by the hybridization selection method. The ordered markers were used to examine the two separated copies of chromosome 22 in the somatic hybrid cell lines. In some cases, we were able to map the chromosome breakpoints within a single cosmid. A 480-kb critical region for VCFS has been delineated, including the genes for GSCL, CTP, CLTD, HIRA, and TMVCF, as well as a number of novel ordered ESTs.
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U2 - 10.1086/515508
DO - 10.1086/515508
M3 - Article
C2 - 9326327
AN - SCOPUS:16944364251
SN - 0002-9297
VL - 61
SP - 620
EP - 629
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -