A novel GLI3 mutation affecting the zinc finger domain leads to preaxial-postaxial polydactyly-syndactyly complex

Polydactyly, one of the most common congenital hand/foot malformations encountered in clinical genetics [1],[2], can occur as an isolated entity or as part of pleiotropic developmental anomaly syndromes [3]. Post-axial polydactyly is far more common than pre-axial and central polydactyly; occasionally, concomitant syndactyly is seen with some forms of polydactyly [2]. The GLI3 protein is a zinc finger transcription factor expressed early in development [4]. It is required for the specification of dorsal cell types and for suppression of ventral cell types in the forebrain [5]. GLI3 expression in the anterior half of the limb buds appears to play an important role in suppressing digit formation [5]. These observations, together with the diverse phenotypes resulting from molecular defects in GLI3, serve as a classical example of pleiotropy: GLI3 mutations are known to cause different clinical entities: Greig Cephalopolysyndactyly Syndrome (GCPS) (MIM ID #175700), Pallister-Hall Syndrome (MIM ID #146510), Acrocallosal Syndrome (MIM ID #200990), Pre-axial Polydactyly type IV (MIM ID #174700) and Post-axial Polydactyly type A (MIM ID #174200). The great majority of known GLI3 mutations cause loss of function [4]. Some reports describe GLI3 mutations as a cause of isolated polydactyly [6], while others consider all GLI3 mutations as causing polydacyly within the GCPS spectrum [7]. It has been suggested that mutations in different domains of the gene underlie the different evolving phenotypes, and that mutations 5' to or within the zinc finger domain (ZFD) of GLI3 specifically cause GCPS [6],[8]. The classic clinical presentation of GCPS is a triad of polysyndactyly, macrocephaly and hypertelorism [9]. Here we report a new heterozygous missense mutation in the zinc finger domain of GLI3 leading to a variable phenotype presenting in some cases as an isolated polydactyly-syndactyly complex.

In the kindred we describe, the OFC and IPD findings possibly stem from intrafamilial variability. The craniofacial manifestations of GCPS are highly variable and not all patients with GCPS have obvious macrocephaly [9] as observed in the family described here. In fact, the mild end of the GCPS spectrum is a continuum with isolated polydactyly [7]. Thus, in some cases there is unclear clinical delineation of GCPS versus non-syndromic polydactyly. The effects of truncating mutations (leading to loss of functional regions) on digit number and identity were largely discussed in the context of GLI3's role as mediator of the hedgehog pathway, whereas connection between defect in the DNA binding domain (DBD) and the phenotype of our pedigree is more elusive. Besides the posterior Hoxd genes, other factors known to be downstream of GLI3 are FGF8, FGF4, GREM1, HAND2 and JAG1[12]. It is plausible that changes in expression patterns of these GLI3 targets (as a result of an obstructed DBD) can contribute to the polydactyly phenotype. Both the precise mechanism through which the specific mutation leads to the disease phenotype, and the molecular mechanisms underlying the familial phenotypic variability are yet to be elucidated.

In summary, we describe a large kindred with a novel heterozygous GLI3 ZFD domain missense mutation leading to polydactyly-syndactyly complex. The phenotype described is within the wide range of phenotypic spectrum of GCPS established by Biesecker [13]. With recent emerging evidence of GLI3 mutations causing non-syndromic limb defects [14],[15], our data highlight the fact that a GLI3 mutation within the ZFD domain can cause a mild form of GCPS with no prominent facial dysmorphism. This report strengthens the need to screen for GLI3 mutations in patients with polydactyly-syndactyly phenotype, even when syndromic features are not evident.

MV carried out the molecular genetic studies and drafted the manuscript. YL was involved in acquisition and analysis of clinical data and helped drafting the manuscript. OSB conceived and coordinated the study and took part in writing the manuscript. All authors read and approved the final manuscript.