Linkage study in families with posterior helical ear pits and Wiedemann-Beckwith syndrome

The Wiedemann-Beckwith syndrome (WBS) is defined by a group of anomalies, i ncluding macrosomia, macroglossia, omphalocele, and ear creases. Several mi nor anomalies have also been reported in the syndrome, including posterior helical ear pits (PHEP). Two independent linkage studies of pedigrees with autosomal dominant inheritance have shown linkage of WBS to 11p15.5 markers . Further confirming the location of WBS to this location is the finding of 11p15.5 duplications and translocations, as well as uniparental disomy for a small area of 11p15.5. In this study, members of previously described fa milies exhibiting autosomal dominant inheritance of the PHEP phenotype were genotyped for three markers in the 11p15.5 region. These three markers wer e in the insulin-like growth factor (IGF2), insulin (INS), and tyrosine hyd roxylase (TH) region. The data were examined by linkage analysis using the same genetic model used previously to demonstrate linkage of WBS to markers on chromosome 11p15.5: an autosomal dominant model with a penetrance of 0. 90 and a gene frequency of 0.001. In one large pedigree, linkage analysis o f the 11p15.5 markers excluded the PHEP phenotype from the IGF2, INS, and T H region. In the four other pedigrees examined, the marker loci were not su fficiently informative or the pedigrees did not provide sufficient power to exclude linkage from this region. The strongest evidence against linkage o f the PHEP phenotype to 11p15.5 was evident by inspection of the segregatio n of the haplotypes of the markers in the pedigrees. In two informative ped igrees, relatives with the PHEP phenotype did not share the same haplotype of markers identical by descent. Our results show that the PHEP phenotype i s not linked to chromosome 11p15.5 in the informative families tested. In t he families examined, there are not enough individuals with WBS to determin e if WBS was linked to 11p15.5 in these families. Although locus heterogene ity has not been demonstrated in WBS, it is possible that a second WBS locu s exists and that the PHEP phenotype in these families is linked to a secon d WBS locus. Alternatively, the PHEP phenotype may occur independently of W BS so that the association of WBS and PHEP in our pedigrees may, in fact, r epresent causal heterogeneity. (C) 2001 Wiley-Liss, Inc.