关键词: 颌骨长骨发育不良, 全外显子组测序, ANO5, 变异

Abstract: Objective To identify the clinical features and pathogenic variants in two unrelated families with gnathodiaphyseal dysplasia (GDD), a rare genetic bone disorder. Methods Facial and limb deformities and skeletal morphology were observed in the probands and their family members. Peripheral blood samples (3-4 mL) were collected from the probands and their parents. Genomic DNA was extracted by standard phenol-chloroform method. Whole exome sequencing (WES) was performed to screen for candidate pathogenic gene variants of the probands. PCR-Sanger sequencing was used to validate the candidate pathogenic variants in the probands and their family members. The pathogenic variants responsible for GDD in the target families were determined through co-segregation of the pathogenic variants in the affected families, evolutionary conservation at the mutation sites,population allele frequency analysis and bioinformatics analysis. Results Heterozygous missense variants in the ANO5 gene were identified in both GDD probands. In family 1, the pathogenic variant was c.1 066T＞G located in the exon 11 of the ANO5 gene, while in family 2, the pathogenic variant was c.1 553G＞A located in the exon 15 of the ANO5. These two variants resulted in the substitutions of amino acid cysteine with glycine at position 356 (p.Cys356Gly) and amino acid glycine with glutamic acid at position 518 (p.Gly518Glu) in the ANO5 protein, respectively. Conclusions This study first identified the pathogenic variant c.1 066T＞G (p.Cys356Gly) in Chinese population, provided important evidence for prediction of disease prognosis and development of potential prenatal genetic diagnosis.

Key words: gnathodiaphyseal dysplasia, whole exome sequencing, ANO5, variants