Abstract
BackgroundNonsyndromic 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.MethodsWe 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.ResultsWe 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.ConclusionOur 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.
Highlights
Cleft lip with or without cleft palate is a common birth defect found in more than 300 recognizable syndromes, but more often it is observed as an isolated birth defect (~70%) (Calzolari et al, 2007) called non‐syndromic cleft lip with or without cleft palate (NSCL/P)
With the development of genomic technologies, the utilization of genome‐wide association studies (GWAS), candidate genes, and animal models have led to a deeper insight into the etiology of NSCL/P (Dixon et al, 2011)
For the novel GLI2 (NM_005270.4) mutation we identified, which has not been reported in the databases, we further performed Sanger sequencing for validation of the minor allele frequency (MAF) on 31 unaffected Chinese subjects
Summary
Beijing Municipal Natural Science Foundation, Grant/Award Number: 7182184; National Natural Science Foundation of China, Grant/Award Number: 81870747 and 81860194; Fund for Fostering Young Scholars of Peking University Health Science Center, Grant/ Award Number: BMU2018PY025
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