Patients: Jewish Moroccan kindred presented with apparently autosomal dominant heredity of polydactyly with variable degrees of mild macrocephaly.
Study objectives: Elucidating the molecular basis of the phenotype in the affected family using linkage analysis
Methods, Following Soroka Medical Center IRB approval and informed consent, blood samples were obtained from 13 affected and 6 unaffected family members. Genomic DNA was extracted by routine techniques. Linkage to genes known to be associated with isolated polydactyly was tested and Sanger sequencing was done.
Results: Polymorphic markers defined a haplotype at the GLI3 locus, that was shared by all affected family members. Sequencing of all GLI3 exons and comparison to the published GLI3 sequence identified a heterozygous missense mutation in the zinc-finger domain (exon 12: c.1802A>G, p.His601Arg). This novel mutation was found in all affected individuals and not in unaffected family members, demonstrating full penetrance yet variable expression of the phenotype.
Conclusion: We thus unravel a novel GLI3 mutation and demonstrate the phenotypic variability in a large kindred with Greig Cephalopolysyndactyly Syndrome.
