A novel frameshift mutation of the GLI3 gene in a family with broad thumbs with/without big toes, postaxial polydactyly and variable syndactyly of the hands/feet

To the Editor : Mutations of the GLI3 gene lead to a wide variety of phenotypes such as Greig cephalopolysyndactyly (GCPS), Pallister–Hall syndrome (PHS), postaxial polydactyly (PAP) types A/B, and preaxial polysyndactyly (PPD) type IV (1–7). The main clinical features of these phenotypes are summarized in Table 1. The GLI3 protein may be divided into three parts (Fig. 1). The part towards the N-terminal contains the zinc finger domain (ZFD). Mutations that predict truncation before or within the ZFD result in GCPS. These are considered as null mutations (haploinsufficiency) caused by loss of the zinc finger DNA-binding domain (1, 2). Patients with PHS have protein truncation after the ZFD but before domain 3. Truncations in this middle part of the protein results in abundance of a constitutive, repressor form of GLI. This skews the balance of activator (GLI3A) vs repressor (GLI3R) forms of GLI3 in the limb bud. Mutations that predict truncations in the carboxy terminal part of the GLI3 protein cause a variable degree of loss of the transactivation domain of GLI3, and this result in a variable phenotype including GCPS, PAP types A and B, and PPD type IV (1–7). We report on a family with a novel frameshift mutation of the GLI3 gene which predicts truncation in the N-terminal third of the protein. However, none of the affected family members had craniofacial