NovelGLI3pathogenicvariants in complex pre- and postaxial polysyndactyly and Greig cephalopolysyndactyly syndrome

Polydactyly is a limb malformation and can occur as nonsyndromic polydactyly, syndromic polydactyly, or along with other limb defects. A few genes have been identified that cause various forms of syndromic and nonsyndromic polydactyly, of whichGLI3has been extensively explored. In the present study,GLI3gene was screened by direct resequencing in 15 polydactyly cases with or without other anomalies.GLI3screening revealed two novel pathogenic variants, NM_000168.6:c.3414delC [p.(H1138Qfs*68)] and NM_000168.6:c.1862C>T [p.(P621L)], found in two unrelated cases of familial complex pre- and postaxial polysyndactyly and sporadic Greig cephalopolysyndactyly syndrome (GCPS), respectively. The first pathogenicGLI3variant, NM_000168.6:c.3414delC, causes premature protein truncation at the C-terminal domain of GLI3. Alternatively, the second pathogenic variant, NM_000168.6:c.1862C>T, lies in the DNA binding domain of GLI3 protein and may affect its hydrophobic interaction with DNA. Both pathogenicGLI3variants had reduced transcriptional activity in HEK293 cells that likely had led to haploinsufficiency and, consequently, the clinical phenotypes. Overall, the present study reports a novel familial case of complex pre- and postaxial polysyndactyly and the underlying novel pathogenicGLI3variant expanding the clinical criteria forGLI3mutational spectrum to complex pre- and postaxial polysyndactyly. Furthermore, this study also reports a novelGLI3pathogenic variant linked to GCPS, highlighting the known genotype-phenotype correlation.

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