A novel frameshift mutation GLI3c.1826delG in a Greig-cephalopolysyndactyly syndrome patient with nontypical preaxial polydactyly: A case report

Typical Greig cephalopolysyndactyly (GCPS) is a rare, autosomal dominant congenital limb malformation that is characterized by macrocephaly, ocular hypertelorism, preaxial polydactyly with or without postaxial polydactyly, and cutaneous syndactyly. Hypoplasia or agenesis of the corpus callosum, developmental delay, intellectual disability, or seizures have also been observed in a few patients with GCPS. The frequency of GCPS syndrome is approximately 1–9/1,000,000 worldwide. GCPS is caused by GLI3 mutations that lead to functional haploinsufficiency in patients. In the present study, we enrolled a 7-year-old girl from an Eastern Indian population. The patient had clinical features of macrocephaly, ocular hypertelorism, a broad and flattened nasal bridge, thumb duplication in the left hand, a broad thumb in the right hand and bilateral symmetrical preaxial polydactyly in both feet (hallucal polydactyly). Patients with uncommon or nontypical phenotypes, such as preaxial polydactyly, in which extra toes (or hallux) were located at a right angle (90 ⁰⁾ from rest toes in both feet and low-set ears, were observed. This patient was diagnosed and confirmed to be a GCPS patient. Resequencing of the GLI3 gene has identified a novel and pathogenic frame-shift mutation, GLI3 c.1826delG, in the heterozygous condition in zinc finger domain within one-third of the full-length GLI3 protein, which caused GCPS phenotypes. The frameshift mutation GLI3 c.1826delG alters the whole trial and sequence of the protein, followed by the generation of a stop codon within the zinc finger domain and premature truncation of the GLI3 protein. The GLI3 c.1826delG mutation leads to haploinsufficiency of the GLI3 full-length protein. The parents were also screened for the GLI3 c.1826delG mutation, and a normal genotype was confirmed to be a de novo mutation in the proband (patient). The present study revealed that the frameshift truncation mutation GLI3 c.1826delG is a pathogenic genetic variant located in the zinc finger domain within one-third of the full length GLI3 protein, which supports the genotype–phenotype correlation in GCPS patients reported previously.