MOLECULAR-GENETIC ANALYSIS OF THE 3P--SYNDROME

Molecular genetic analysis of five cases of 3p - syndrome (del(3)(qter -->p25:)) was performed to investigate the relationship between the mo lecular pathology and clinical phenotype. Fluorescence in situ hybridi zation studies and analysis of polymorphic DNA markers from chromosome 3p25 - p26 demonstrated that all four informative cases had distal de letions. However, the extent of the deletion was variable: in two pati ents with the most extensive deletions the deletion breakpoint mapped between RAF1 and D3S1250, in one patient the deletion breakpoint was b etween D3S1250 and D3S601, and in two patients the deletion commenced telomeric to D3S601 (and telomeric to D3S1317 in one of these). All fi ve patients displayed the classical features of 3p - syndrome (mental retardation, growth retardation, microcephaly, ptosis and micrognathia ) demonstrating that loss of sequences centromeric to D3S1317 is not r equired for expression of the characteristic 3p - syndrome phenotype. The three patients with the most extensive deletions had cardiac septa l defects suggesting that a gene involved in normal cardiac developmen t is contained in the interval D3S1250 and D3S18. The PMCA2 gene is co ntained within this region and deletion of this gene may cause congeni tal heart defects. At least three patients were deleted for the von Hi ppel - Lindau (VHL) disease gene although none had yet developed evide nce of VHL disease. We conclude that molecular analysis of 3p - syndro me patients enhances the management of affected patients by identifyin g those at risk for VHL disease, and can be used to elucidate the crit ical regions for the 3p - syndrome phenotype.