The 18q^- syndrome: Analysis of chromosomes by bivariate flow karyotyping and the PCR reveals a successive set of deletion breakpoints within 18q21.2-q22.2

The 18q^- syndrome is one of several terminal deletion disorders that occur in humans. Previous G-banding studies suggest that the loss of a critical band, 18q21.3, results in mental retardation, craniofacial anomalies, and metabolic defects. However, it is difficult to reconcile the consistent loss of a single region with the large variability in clinical phenotype. The purpose of this study was to reassess the extent of chromosomal loss in a cohort of 17 18q^- syndrome patients by using fluorescent-activated chromosome sorting, PCR, and FISH. Bivariate flow karyotypes revealed heterogeneity among the deletions; they ranged in size from 9 to 26 Mb. To confirm this heterogeneity at a molecular level, deleted and normal chromosomes 18 of six patients were collected by flow sorting, preamplified by random priming, and assayed for marker content by the PCR. This analysis defined five unique breakpoints among the six patients. We conclude that the terminal deletions in the 18q^- syndrome occur over a broad region spanning the interval from 18q21.2 to 18q22.2. Our results suggest that the variability in clinical phenotype may be more representative of a contiguous-gene syndrome with a baseline deficit of 18q22.2-qter than of the loss of a single critical region within 18q21.3.