Genotype-phenotype correlations and clinical diagnostic criteria in Wolf-Hirschhorn syndrome

We report on a clinical-genetic study of 16 Wolf-Hirschhorn syndrome (WHS) patients. Hemizygosity of 4p16.3 was detected by conventional prometaphase chromosome analysis (11 patients) or by molecular probes on apparently norm al chromosomes (4 patients), One patient had normal chromosomes without a d etectable molecular deletion within the WHS "critical region." In each dele ted patient, the deletion was demonstrated to be terminal by fluorescence i n situ hybridization (FISH), The proximal breakpoint of the rearrangement w as established by prometaphase chromosome analysis in cases with a visible deletion. It was within the 4p16.1 band in six patients, apparently coincid ent with the distal half of this band in five patients. The extent of each of the four submicroscopic deletions was established by FISH analyses with a set of overlapping cosmid clones spanning the 4p16.3 region. We found amp le variations in both the size of the deletions and the position of the res pective breakpoints, The precise definition of the cytogenetic defect permi tted an analysis of the genotype-phenotype correlations in WHS, leading to the proposal of a set of minimal diagnostic criteria, which in turn may fac ilitate the selection of critical patients in the search for the gene(s) re sponsible for this disorder. We observed that genotype-phenotype correlatio ns in WHS mostly depend on the size of the deletion, a deletion of <3.5 Mb resulting in a mild phenotype, in which malformations are absent, The absen ce of a detectable molecular deletion is still consistent with a WHS diagno sis. Based on these observations a "minimal" WHS phenotype was inferred, th e clinical manifestations of which are restricted to the typical facial app earance, mild mental and growth retardation, and congenital hypotonia, (C) 2000 Wiley-Liss, Inc.