一家系遗传性多发性骨软骨瘤的致病突变基因鉴定

Identification of pathogenic mutant gene in a family with hereditary multiple exostosis

目的鉴定一家系遗传性多发性骨软骨瘤(HME)的致病突变基因。方法抽取该家系先证者及家系成员外周血,进行血液常规及生化项目检查,提取基因组DNA,应用全外显子组测序技术进行检测,通过生物信息学分析筛选致病变异,确定突变位点,用PCR-Sanger测序法进行突变验证。结果该家系5例患者均存在EXT1基因第6外显子c.1468dupC(p.Leu490Profs*31)杂合移码突变,表型正常家系成员未检测到该突变,符合家系基因型—表型共分离。结论导致该家系患者发病的致病突变为EXT1基因c.1468dupC(p.Leu490Profs*31)杂合移码变异,该结果进一步扩展了EXT1基因的突变谱,同时也为家系中患者的遗传咨询和产前基因诊断奠定了分子基础。

Objective To analyze the pathogenic mutant gene in a family with hereditary multiple exostosis(HME).Methods We drew peripheral blood from probands and family members in this family,and the blood routine and biochemical examination were performed to extract the genomic DNA,and whole-exome sequencing(WES)technique was used to detect 5 patients in this family.The pathogenic mutation was identified by bioinformatics analysis,and the mutant site was verified by PCR-Sanger sequencing.Results The sequencing results showed that all these five patients in this family had a heterozygous duplicated mutation c.1468 dupC(p.Leu490 Profs*31)in the exon 6 of the EXT1 gene.The mutation was not detected in the family members with normal phenotype,which was consistent with the family genotype-phenotype co-separation.Conclusion The heterozygous frameshift mutation c.1468 dupC(p.Leu490 Profs*31)of EXT1 gene is the pathogenic mutation leading to the disease of the HME family.These results further expand the mutational spectrum of EXT1 gene,and provide a molecular basis for genetic counseling and prenatal genetic diagnosis of patients in their pedigree.