Novel GLI3 Mutations in Chinese Patients with Non-syndromic Post-axial Polydactyly

Abstract

Background: Polydactyly, characterized by supernumerary digits in the upper or lower extremities, is the most common congenital digital abnormalities. It derives from the defective patterning of anteroposterior axis of the developing limb, with various etiology and clinical heterogeneity. The patients with post-axial polydactyly type A (PAPA) have the typical symptom of a well-formed supernumerary digit outside the fifth digit. Objective: The aim of present study was to identify the causative mutations of two unrelated Han Chinese patients with non-syndromic PAPA. Methods: Two unrelated Han Chinese patients and 100 ethnicity-matched, unrelated normal controls were recruited for this study. BGISEQ-500 exome sequencing was performed in the two patients, followed by validation in the patients and 100 controls by using Sanger sequencing. Results: Two mutations in the GLI family zinc finger 3 gene (GLI3), including a frameshift mutation c.3437_3453delTCGAGCAGCCCTGCCCC (p.L1146RfsX95) and a nonsense mutation c.3997C>T (p.Q1333X), were identified in two patients but were absent in the 100 healthy controls. Conclusion: The two GLI3 mutations, p.L1146RfsX95 and p.Q1333X, may account for non-syndromic PAPA in the two patients, respectively. The findings of this study may expand the mutational spectrum of GLI3-PAPA and provide novel insights into the genetic basis of 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.…”

Identification of truncated variants in GLI family zinc finger 3 (GLI3) associated with polydactyly

“…Several causative genes have been reported to be associated with IPD, including the GLI family zinc nger 3 gene (GLI3, OMIM 165240), zinc nger protein 141 gene (ZNF141, OMIM 194648), IQ domain-containing protein E gene (IQCE, OMIM 617631), GLI family zinc nger 1 gene (GLI1, OMIM 165220), Family with sequence similarity 92, member A (FAM92A, OMIM 617273) and Centrosomal protein 68 (CEP68, OMIM 616889). (3)(4)(5)(6)(7)(8). Among these genes, GLI3 plays a vital role in limb development.…”