PRECISE LOCALIZATION OF 3P25 BREAKPOINTS IN 4 PATIENTS WITH THE 3P-SYNDROME

In patients with the 3p- syndrome, hemizygous deletion of 3p25-pter is associated with profound growth failure, characteristic facial featur es, and mental retardation. We performed a molecular genetic analysis of 3p25 breakpoints in four patients with the 3p- syndrome, and a fift h patient with a more complex abnormality, 46,XY,der(3)t(3;?) (p25.3;? ). EBV transformed lymphoblasts from each of the patients were initial ly characterised using fluorescent in situ hybridisation (FISH) and po lymorphic microsatellite analyses. The 3p- chromosome from each patien t was isolated from the normal chromosome 3 in somatic cell hybrid lin es and subsequently analysed with polymorphic and monomorphic PCR ampl ifiable markers from 3p25. The analysis clearly shows that all five br eakpoints are distinct. Furthermore, we have identified yeast artifici al chromosomes that cross the 3p25 breakpoints of all four 3p-patients . Two of the patients were deleted for the von Hippel-Lindau (VHL) tum our suppressor gene, although neither has yet developed evidence of VH L disease. The patient with the most centromeric breakpoint, between D 3S1585 and D3S1263, had the most severe clinical phenotype including a n endocardial cushion defect that was not observed in any of the four patients who had more telomeric breakpoints. This study should provide useful insights into critical regions within 3P25 that are involved i n normal human growth and development.