ClinVar

In 2 affected individuals (patients 1 and 2) from a large multiply consanguineous Turkish pedigree with postaxial polydactyly of the hands and/or feet (PAPA8; 618123), Palencia-Campos et al. (2017) identified homozygosity for a c.2340G-A transition (c.2340G-A, NM_005269.2) in the last exon of the GLI1 gene, resulting in a trp780-to-ter (W780X) substitution and a protein lacking the transactivation domain. The proband had hexadactyly of the hands and feet, whereas the affected distant relative had hexadactyly only of the hands. Another distant relative with hand involvement (patient 3) was heterozygous for the mutation, which he inherited from his unaffected mother, and an older relative with a history of hand involvement that was surgically corrected in infancy did not carry the mutation. The authors suggested that patient 3 might carry hypomorphic variants in another gene, or that mutation in a different gene might be responsible for the phenotype in patients 3 and 4. Functional analysis in cell cultures and in vivo assays revealed severely impaired transcriptional activity of the W780X mutant compared to wildtype. In addition, reduced expression of the GLI1 target PTCH1 (601309) was observed in patient fibroblasts after chemical induction of the hedgehog (see 600725) pathway. The variant was not found in dbSNP, ExAC, EVS, gnomAD, 1000 Genomes Project, or Kaviar databases.