三个遗传性多发性骨软骨瘤家系致病基因突变分析

Genetic mutation analysis in three pedigrees with hereditary multiple exostosis

目的:对3个遗传性多发性骨软骨瘤(HME)家系行致病基因检测,为优生、遗传咨询和产前诊断提供依据。方法:收集2018年1月至2020年11月就诊于河南省人民医院遗传与产前诊断中心的3个遗传性多发性骨软骨瘤家系,对家系进行详细的病史采集,签署知情同意书后,收集家系成员外周静脉血,对先证者行全外显子组测序(WES),发现可疑致病位点后,采用Sanger测序对家系成员候选致病变异进行验证及家系共分离分析,结合ACMG指南,对突变进行致病性判断。结果:全外显子组测序分别在3个家系先证者中检出EXT1基因c.1056+2T>C突变、c.369dupA(p.G124fs)突变和EXT2基因c.1171C>T(p.Q391^(*))突变。共分离验证后发现:3个家系中的患者均存在相应突变,而表型正常的家系成员未检测到突变,符合基因型-表型共分离。结合ACMG指南,上述3种突变可分类为致病性突变。结论:EXT1基因c.1056+2T>C、c.369dupA突变和EXT2基因c.1171C>T突变是导致3个家系罹患骨软骨瘤的病因。

Objective:To detect the pathogenic gene of the three pedigrees with hereditary multiple exostosis,and to provide evidences for genetic counselling and prenatal diagnosis.Methods:The three families were admitted to the Institute of Medical Genetics of Henan Provincial People′s Hospital due to hereditary multiple exostosis from January 2018 to December 2020.Detail medical history and the blood samples of the family members were collected after they signed the informed consent forms.The pathological mutations were selected from the proband using whole exome sequencing(WES).Sanger sequencing was used to conduct the co-segregation analysis of the family members.The pathogenicity of the mutation was analyzed in combination with ACMG guidelines.Results:The EXT1 gene c.1056+2T>C mutation,c.369dupA(p.G124fs)mutation and the EXT2 gene c.1171C>T(p.Q391&(*))mutation were detected in the probands through whole exome sequencing.The same mutations were found in the patients from these three families,while the mutation was not detected among the healthy family members.These variations have co-segregated with the disease phenotype.According to ACMG guidelines,all mutations in these three families meet the criteria of pathogenic variations.Conclusion:The EXT1 gene c.1056+2T>C mutation,c.369dupA(p.G124fs)mutation and the EXT2 gene c.1171C>T(p.Q391^(*))mutation were identified to be responsible for hereditary multiple exostosis in these families.