A Novel Frameshift Mutation of GLI3 Causes Isolated Postaxial Polydactyly

Abstract

Background GLI3 encodes a transcription factor in the sonic hedgehog signaling pathway, which is essential in regulating the human limb bud development, especially on the anteroposterior axis. Mutations in GLI3 have been confirmed to be associated with various human congenital malformations, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, and isolated polydactyly. A robust gene-phenotype relationship between GLI3 and Greig cephalopolysyndactyly syndrome and Pallister-Hall syndrome has been well elucidated, and less is known about GLI3 mutation–caused isolated polydactyly. This study intended to perform a mutation analysis of GLl3 in a family with isolated polydactyly. Methods A 3-generation Chinese family with 19 members was recruited in this study, of which the proband and her mother were affected with polydactyly. The whole-exon sequencing was performed to find mutations, and Sanger sequencing was performed to validate the mutations. Results We found a novel heterozygous frameshift mutation of GLI3 (c.1180C > TT, p.P394fs18x) in the proband of a Chinese family with isolated postaxial polydactyly. No mutation was detected in the proband's father or another 2 patients with sporadic preaxial polydactyly. Conclusions By systematically reviewing the gene-phenotype relationship, we found that GLI3 p.P394fs18x mutation might be specific for isolated postaxial polydactyly.

Novel frameshift mutations of ANKUB1, GLI3, and TAS2R3 associated with polysyndactyly in a Chinese family

“…It has been demonstrated that GLI3 possesses a dual function, including a transcriptional activator of SHH signaling pathway by phosphorylated full‐length GLI3 and a repressor by C‐terminally truncated CLI3. Recently, several novel mutations of GLI3 have been identified in the patients with PD, including mutation c. 1622C > T (Zou et al, 2019), c.2148delA (Zhao, Xu, Liu, & Li, 2019), c.3437_3453delTCGAGCAGCCCTGCCCC, and c.3997C > T (Chen et al, 2019), c.1180C > TT (Ni et al, 2019). Therefore, our results suggested that this frameshift mutation of GLI3 might be a main reason for preaxial PD type IV phenotype in this Chinese family.…”

Exome sequencing revealed a novel loss‐of‐function variant in the GLI3 transcriptional activator 2 domain underlies nonsyndromic postaxial polydactyly

“…Several studies have elucidated genotype–phenotype correlation in terms of location of the mutation in particular domain and the resulting phenotype (Ni et al, ; Wang et al, ). Currently, most GLI3 mutations causing syndromic and nonsyndromic phenotypes are loss‐of‐function variants (Ni et al, ).…”

“…Several studies have elucidated genotype–phenotype correlation in terms of location of the mutation in particular domain and the resulting phenotype (Ni et al, ; Wang et al, ). Currently, most GLI3 mutations causing syndromic and nonsyndromic phenotypes are loss‐of‐function variants (Ni et al, ). Mutations in N‐terminal and the C‐terminal regions are mostly associated with the GCPS, while the PHS phenotype mostly results due to mutations in the central part of the protein (Demurger et al, ; Jamsheer et al, ).…”

Novel GLI3 variant causes Greig cephalopolysyndactyly syndrome in three generations of a Lithuanian family

“…At the same time, a greater spectrum of pathogenic variants located before 1998 nt and after 3481 nt of GLI3 cDNA cause loss of function and manifest in GCPS (Furniss, Critchley, Giele, & Wilkie, ; Johnston et al, ; Kalff‐Suske et al, ). The underlying mechanism of the influence of the location of the variants on different syndromes is still unknown (Ni et al, ). The haploinsufficiency of GLI3 is however proposed to be the main mechanism of the pathogenesis of GCPS.…”