Clinical and genetic studies of limb anomaly syndromes

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This research study encompasses a range of phenotypes that include Pallister-Hall syndrome, the allelic disorder Greig cephalopolysyndactyly syndrome (GCPS), McKusick-Kaufman syndrome (MKS), and Bardet-Biedl syndrome (BBS). The clinical manifestations of these disorders include polydactyly, central nervous system malformations (with or without mental retardation and seizures), craniofacial malformations, and visceral malformations such as renal malformations or congenital heart defects. We study these disorders by a translational approach that begins in the clinic with careful clinical evaluation of the phenotypes by physical examination, imaging studies that include radiographs, ultrasound, MRI and CT scanning. We have shown that BBS and MKS can both be caused by mutations in the same gene. PHS and GCPS are caused by a wide spectrum of mutations in the GLI3 gene. One type of mutations causes PHS (truncations in the middel third of the gene) and any loss of function mutation OR 3' truncation causes GCPS. The severity of the GCPS phenotype, specifically the mental retardation and learning disability, are correlated with the mutations. Patients with larger deletions have a more severe phenotype. We are characterizing a mouse mutant that is a phenocopy of the extra toes Gli3 mouse mutant that is linked to a locus other than Gli3. We are studying this animal because it should shed light on other genes in the Gli3 pathway.