LINKAGE MAPPING AND PHENOTYPIC ANALYSIS OF AUTOSOMAL-DOMINANT PALLISTER-HALL-SYNDROME

Pallister-Hail syndrome is a human developmental disorder that is inhe rited in an autosomal dominant pattern. The phenotypic features of the syndrome include hypothalamic hamartoma, polydactyly, imperforate anu s, laryngeal clefting, and other anomalies. Here we describe the clini cal characterisation of a family with 22 affected members and the gene tic mapping of the corresponding locus. Clinical, radiographic, and en doscopic evaluations showed that this disorder is a fully penetrant tr ait with variable expressivity and low morbidity. By analysing 60 subj ects in two families using anonymous STRP markers, we have established linkage to 7p13 by two point analysis with D7S691 resulting in a lod score of 7.0 at theta=0, near the GLI3 locus. Deletions and translocat ions in GLI3 are associated with the Greig cephalopolysyndactyly syndr ome. Although Greig cephalopolysyndactyly syndrome has some phenotypic overlap with Pallister-Hail syndrome, these two disorders are clinica lly distinct. The colocalisation of loci for these distinct phenotypes led us to analyse GLI3 for mutations in patients with Pallister-Hail syndrome. We have previously shown GLI3 mutations in two other small, moderately affected families with Pallister-Hall syndrome. The linkage data reported here suggest that these larger, mildly affected familie s may also have mutations in GLI3.