Mutational Spectrum of Pallister-Hall Syndrome. L.G. Biesecker¹, J.M. Graham², T. Grebe³, G. Neri⁴, R. Pagon⁵, C. Bonneman⁵, M. Partington⁵, C. Killoran¹. 1) Genetic Dis Res Branch, LGDR/NHGRI/NIH, Bethesda, MD; 2) UCLA, Cedars-Sinai Medical Center; 3) University of Arizona, Phoenix; 4) Universita Cattolica, Rome, Italy; 5) Other Institutions.

   Pallister-Hall syndrome is a human developmental anomaly syndrome that includes hypothalamic hamartoma, polydactyly, bifid epiglottis, and visceral malformations. It is inherited in an autosomal dominant pattern and has been shown to be caused by mutations in the Gli3 zinc finger transcription factor gene. Here we report 11 mutations that cause PHS in addition to the originally described two mutations. These newly reported mutations have been found in sporadic (eight cases) and familial (three cases) occurrences of the disorder. In all cases, the mutation predicts a premature truncation of the GLI3 protein due to 1-19 bp deletions (seven cases), insertions (1 case) or nonsense mutations (three cases). There are no substitutions known to cause PHS. The position of the mutations within the gene ranges from cDNA bp 2146 to 3324, all of which are 3' to the zinc finger encoding domains. These mutations overlap with some truncation mutations that have been associated with apparantly isolated post-axial polydactyly type A (PAP-A). We will review these mutations in light of the molecular models of GLI3 activity and correlate the mutations with the phenotypes of the affected members of the pedigrees.