The Pallister-Hall Syndrome (PHS) includes polydactyly, anal atresia, hypospadias, hypothalamic hamartoma, and panhypopituitarism. It is rare but is interesting because of the development implications of such a spectrum of anomalies. There are several disorders that have related malformations that are thought to be genetically or morphogenetically related to PHS. These include Oral-Facial-Digital type VI MuKusick- Kaufmann syndrome, and others. We have identified 4 families that segregate the PHS phenotype in an autosomal dominant pattern. We have performed clinical and molecular studies on these families to better define the range of phenotypic features in PHS and search for the gene by a linkage approach. To date we have clinically evaluated 10 individuals with PHS and have acquired DNA specimens on nearly 100 persons from families with this disorder. We have mapped this disorder to 7p13 by multipoint linkage analysis with a LOD score of 13.8. This locus contains several interesting candidate genes; specifically the CL13 zinc finger gene and Inhibin-beta-A, an endocrine signaling molecule. GLI3 is the gene that has been implicated in the Greig cephalopolysyndactyly syndrome, a disorder related to PHS. We have nearly completed the determination of the exon- intron boundaries of GLI3 and have screened most of the coding region without detecting any mutations. We have high confidence in our ability to detect mutations as we have detected 4 single base pair polymorphisms in the coding region. We have used these polymorphisms to determine that both alleles of the gene are expressed in persons affected by PHS, in contrast to Greig syndrome, which is associated with haploinsufficiency for GLI3.
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