MOLECULAR DEFINITION OF 22Q11 DELETIONS IN 151 VELO-CARDIO-FACIAL-SYNDROME PATIENTS

Velo-cardio-facial syndrome (VCFS) is a relatively common developmenta l disorder characterized by craniofacial anomalies and conotruncal hea rt defects, Many VCFS patients have hemizygous deletions for a parr of 22q11, suggesting that haploinsufficiency in this region is responsib le for its etiology, Because most cases of VCFS are sporadic, portions of 22q11 may be prone to rearrangement, To understand the molecular b asis 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 similar to 3 Mb del etion, suggesting that sequences flanking the common breakpoints are s usceptible to rearrangement. We found no correlation between the prese nce or size of the deletion and the phenotype. To further define the c hromosomal breakpoints among the VCFS patients, we developed somatic h ybrid cell lines from a set of VCFS patients. An 11-kb resolution phys ical map of a 1,080-kb region that includes deletion breakpoints was c onstructed, incorporating genes and expressed sequence tags (ESTs) iso lated by the hybridization selection method, The ordered markers were used to examine the two separated copies of chromosome 22 in the somat ic hybrid cell lines. Ln some cases, we were able to map the chromosom e breakpoints within a single cosmid, A 480-kb critical region for VCF S has been delineated, including the genes for GSCL, CTP, CLTD, HIRA, and TMVCF, as well as a number of novel ordered ESTs.