Three GLI2 mutations combined potentially underlie non‐syndromic cleft lip with or without cleft palate in a Chinese pedigree

Abstract

Background Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect. Its etiology is complex and it has a lifelong influence on affected individuals. Despite many studies, the pathogenic gene alleles are not completely clear. Here, we recruited a Chinese NSCL/P family and explored the candidate causative variants in this pedigree. Methods We performed whole‐exome sequencing on two patients and two unaffected subjects of this family. Variants were screened based on bioinformatics analysis to identify the potential etiological alleles. Species conservation analysis, mutation function prediction, and homology protein modeling were also performed to preliminarily evaluate the influence of the mutations. Results We identified three rare mutations that are located on a single chromatid (c.2684C > T_p.Ala895Val, c.4350G > T_p.Gln1450His, and c.4622C > A_p.Ser1541Tyr) in GLI2 as candidate causative variants. All of these three mutations were predicted to be deleterious, and they affect amino acids that are conserved in many species. The mutation c.2684C > T was predicted to affect the structure of the GLI2 protein. Conclusion Our results further demonstrate that GLI2 variants play a role in the pathogenesis of NSCL/P, and the three rare missense mutations combined are probably the potential disease‐causing variants in this family.

Orofacial Closure Defects: Forty-Five Genes Associated Cleft Lip and Palate

“…The findings supported the role of CLPTM1(3), NECTIN1 (19), OFC1 (22), SPRY2 (23), THADA (24), SHTN1 (54), NOGGIN (27), TPM1 (30), GREM1 (31), PAX7 (34), SHH (36), SIX3 (37), BRIP1(BACH1) (38), BRCA1 (40), MAFB (26), FOXE1 (42), AXIN2 (43), SNAI1 (46), BRCA2 (40), GLI2 (48), GRHL3 (49), COL21A1 (50), WNT5A (51), TOX3 (52), and SOX9 (52) in the development of a CL ± P malformative phenotype. The findings also revealed that GAD1 (28), ARHGAP29 (39), and DVL2 (43) were regulatory proteins essential for proper development of the face.…”

“…A study conducted on Gli2 in 2019 among Chinese people found the mutation c. 2684C > T_p. Ala895Val plays a role in the pathogenesis of NSCL/P (48).…”

Identification of rare PTCH1 nonsense variant causing orofacial cleft in a Chinese family and an up-to-date genotype-phenotype analysis

“…In our previous work involving identification of the genetic mutations underlying CL/P, 10 , 17 , 18 many variants were left after the traditional screening process, and a manual literature search was required to identify the candidate(s). In this study, we employed a web crawler strategy for the first time to narrow down the list of variants.…”

Truncating and zinc‐finger variants in GLI2 are associated with hypopituitarism

“…We reviewed the literature for comprehensive phenotypic descriptions of individuals with confirmed pathogenic (a) intragenic GLI2 variants and (b) chromosome 2q14.2 deletions encompassing only GLI2 . We re‐evaluated the pathogenicity of previously published GLI2 missense variants (Table 2) (Arnhold et al, 2015; Babu et al, 2019; Bear et al, 2014; Bertolacini et al, 2012; Brauner et al, 2020; Flemming et al, 2013; França et al, 2013; Gregory et al, 2015; Juanes et al, 2016; Meng et al, 2019; Rahimov et al, 2006; Vaaralahti et al, 2012; Vishnopolska et al, 2021). This re‐evaluation was primarily based on population variant frequency in the gnomAD database (Karczewski et al, 2020).…”