Work

The molecular characterization of seven novel GLI family zinc finger 3 (GLI3) variants in Chinese families with limb malformations

Year: 2025

Type: article

Abstract: Background GLI family zinc finger 3 (GLI3) is a transcription factor involved in limb development. GLI3 gene variants have been shown to be associated with several human congenital limb malformations, including Greig's head polydactyly and syndactyly, Pallister–Hall syndrome, non-syndromic postaxial polydactyly (PAP-A/B), and preaxial polydactyly type IV (PPD IV). The aim of this study was to identify GLI3 gene variants in ten Chinese families with limb malformations. Methods Ten Chinese families with limb malformations were recruited. Variant screening in probands was then performed using next generation sequencing, with candidate pathogenic variants verified by polymerase chain reaction (PCR) combined with Sanger DNA sequencing. Variant pathogenicity was evaluated using bioinformatics, evolutional conservation, and disease and mutant allele co-segregation approaches. The biological effects of missense variants were predicted by three-dimensional protein conformation analysis. Results Ten different GLI3 variants were identified, including two missense variants: c.1063G > A (p.Val355Ile) and c.1489C > A (p.Leu497Ile), four nonsense variants: c.2374C > T (p.Arg792*), c.2008C > T (p.Gln670*), c.1096 C > T(p.Arg366*), and c.2029C > T(p.Gln677*), three small deletions: c.600delC (p.Tyr200*), c.1880_1881del(p.His627Argfs*48), and c.811_812delCT(p.Leu271Serfs*5), and a large gross deletion g.42061081_42069739. Seven of these ten variants were not recorded in the Human Gene Mutation Database (HGMD). Conclusions Ten GLI3 variants were successfully identified in families with different limb malformations, and indicate clinical and allelic GLI3 heterogeneity-related limb malformations. This work expands the GLI3 gene-variant landscape and associated clinical disease manifestations, and provides solid evidence for genetic counseling and prenatal gene diagnostics in affected families.

Source: Frontiers in Genetics

DOI: 10.3389/fgene.2025.1650790

Authors: Siyuan Tao, Xuyu Gu, Xiaodong Wang, Xiaofang Shen, Xiuli Zhao

Institutions: Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital, Soochow University, Children's Hospital of Suzhou University

Language: English

Topic: Congenital limb and hand anomalies

Subfield: Developmental Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801