A genetic map of 22Q11 and its application to the study of Di George syndrome

Wendy Janine Fibison, University of Pennsylvania


A genetic linkage map of chromosome 22qll comprising five markers (D22S9, D22S43, D22S57, D22S75, and BCR) has been constructed in CEPH families. Using CILINK all orders are excluded except: D22S9 - D22S43 - D22S57 - D22S75 - BCR. Using Kosambi's mapping function, the markers span 18.8 cM (male), 32.4 cM (female), and 26.4 cM (sex-averaged). Physical mapping places D22S9 centromeric to BCR. Linkage analysis for the marker H162 (D22S68) previously localized to the IGLV region is not possible. Incompatibilities are found in 7 of 27 informative CEPH pedigrees. This apparently results from somatic rearrangement at the IGL locus in the EBV-transformed lymphoblastoid cell lines. Analysis with an IGLC probe supports this interpretation. The IGL locus in 22qll has been bridged using a marker from the more distal BCR region. BCR is linked to D22S75 with a Z max = 5.67 at $\Theta$ max = 0.074. The total genetic distance for this 22qll linkage group is greater than anticipated, suggesting that chromosome 22 undergoes more recombination than average based on its physical size. This genetic map has been used to begin to delineate the critical region for the DiGeorge Syndrome (DGS). Polymorphic and densitometric studies have been conducted on DGS cell lines with deletions of 22qll using probes D22S9, D22S43, D22S57, D22S75. Included in our study are DGS patients with unbalanced translocations involving loss of 22qll (GM2944A, GM3577, GM5401), interstitial deletions in 22qll (KM4987, 7348), and BC1171, a patient with karyotype described as, 46,XX,22P+. Heterozygosity studies demonstrate two alleles for D22S43 in 7248; and two alleles for D22S43 and D22S57 in KM4987, thereby placing both loci in a flanking, but not critical region for DGS. Using the genetic linkage studies, the next most distal locus to D22S57 is D22S75. Polymorphism and densitometric analysis show that D22S75 is deleted in GM2944A, GM5401, 7248, and BC1171. Previous in situ hybridization studies placed the translocation-related DGS breakpoint proximal to IGLC. Thus, the DGS critical chromosomal region (DGCR) must be distal to D22S57 and proximal to IGLC region in 22qll. This study represents the first molecular analysis of DGS probands demonstrating loss of specific DNA sequences for chromosome 22.

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Recommended Citation

Fibison, Wendy Janine, "A genetic map of 22Q11 and its application to the study of Di George syndrome" (1990). Dissertations available from ProQuest. AAI9112559.