一个新PHEX基因变异导致X连锁遗传性低血磷性佝偻病的家系遗传学分析  

Genetic analysis of an X-linked Hypophosphatemic rickets pedigree caused by a novel pathogenic variant in PHEX gene

作　　者：康可 张玉薇 张闻宇[3] 侯巧芳[2] 娄桂予[2] KANG Ke;ZHANG Yu-wei;ZHANG Wen-yu;HOU Qiao-fang;LOU Gui-yu(Department of Joint and Sports Medicine,Zhengzhou Yihe hospital,Zhengzhou 450018,China;Institution of Medical Genetics of He'nan Provincial People's Hospital,Zhengzhou 450002,China;Department of Endocrinology and Metabolism,Zhengzhou People's Hospital,Zhengzhou 450002,China)

机构地区：[1]郑州颐和医院关节与运动医学科,郑州450018 [2]河南省人民医院医学遗传研究所,郑州450002 [3]郑州人民医院内分泌与代谢科,郑州450002

出　　处：《中华骨质疏松和骨矿盐疾病杂志》2024年第3期213-220,共8页Chinese Journal Of Osteoporosis And Bone Mineral Research

基　　金：河南省医学科技攻关计划省部共建项目(SBGJ202302005);河南省中青年卫生健康科技创新领军人才培养项目(YXKC2021001)。

摘　　要：目的以一个临床表型为低血磷性佝偻病(hypophosphatemic rickets,HR)的家系为研究对象,通过全外显子组测序寻找该家系的致病变异基因,并分析变异的致病性。方法收集HR家系临床资料,进行生化检测。提取先证者DNA,进行临床全外显子组测序,并针对可疑致病变异对家系所有成员进行PCR扩增,Sanger测序验证。预测变异的致病性及对蛋白质空间结构的影响。结果该家系共3代,先证者是一位26岁女性,先证者母亲、先证者及其儿子和女儿为患者,临床表现为O型腿、鸡胸、低磷血症,骨骼X线检查、生化检测、成纤维细胞生长因子23(fibroblast growth factor 23,FGF23)检测结果提示低血磷性佝偻病。临床全外显子组测序发现PHEX(NM_000444)c.2193dupT的插入移码杂合变异,该变异可导致编码第732位的天冬酰胺变异为终止密码子(p.N732*),从而出现了蛋白质截短。先证者的母亲、儿子及女儿PHEX基因均存在该变异。根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)对变异的分类标准,分级为可能致病性变异。经查阅文献及查找人类基因突变数据库,该变异均未被报道或收录。结论本研究发现了一个PHEX新致病变异,为该家系的临床诊断和治疗及遗传咨询提供了实验依据。Objective To investigate a pedigree with the clinical phenotype of hypophosphatemic rickets(HR),and the pathogenic variants was detected by whole-exome sequencing(WES)and analyzed by bioinformatics.Methods The clinical data,biochemical indicators of the HR family members were evaluated.DNA of the proband was extracted for WES experiment.PCR-Sanger sequencing and bioinformatics were performed on all members of the family to analyze the suspected pathogenic variants.The pathogenicity of mutations and their effects on protein spatial structure were predicted.Results Three generations of this family were investigated,the proband was a woman of 26 years old,and her mother and her son and daughter were diagnosed as HR by manifestations of O-shaped legs,chicken chest and low blood phosphorus level,as well as skeletal X-ray characters and high serum fibroblast growth factor 23(FGF23)level.WES identified a c.2193dupT insertion-shift heterozygous variant in PHEX(NM_000444),which resulted in a truncation of protein formation at position of 732 amino acid(p.N732*).All patients including the proband,her mother,the son and daughter carried this variant,which was classified as a likely pathogenic variant according to the new American College of Medical Genetics and Genomics(ACMG)criteria.After reviewing the literature and searching the human gene mutation database,this variant was not reported.Conclusion A novel pathogenic variant of PHEX gene is identified in this study,which provides an experimental basis for the clinical diagnosis,treatment and genetic counseling for the family.

关 键 词：X连锁遗传性低血磷性佝偻病 PHEX基因 基因变异 

分 类 号：R589.5[医药卫生—内分泌]