全外显子测序对一例甲状腺激素抵抗综合征患者THRβ基因突变的研究  

Research on THRβ gene mutation in a patient with thyroid hormone resistance syndrome using whole-exome sequencing

作　　者：加衣达·努拉里 万月月 赵双霞[1] 宋怀东[1] Jiayida Nulali;Wan Yueyue;Zhao Shuangxia;Song Huaidong(The Core Laboratory in Medical Center of Clinical Research,Department of Molecular Diagnostics,Shanghai Ninth People′s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200001,China)

机构地区：[1]上海交通大学医学院附属第九人民医院分子诊断科,中心实验室200001

出　　处：《中华内分泌代谢杂志》2023年第4期353-357,共5页Chinese Journal of Endocrinology and Metabolism

摘　　要：目的对1例甲状腺激素抵抗综合征(resistance to thyroid hormone syndrome,RTH)患者进行临床分析及基因变异检测,并探讨其致病机制。方法收集先证者的临床资料,抽取先证者外周血基因组DNA进行全外显子测序筛选致病基因,并通过Sanger测序进行验证,同时利用生物信息学软件对变异位点进行蛋白功能分析。结果先证者表现为胸闷、心悸和持续性房颤等临床表现,血清游离三碘甲状腺原氨酸(FT3)、游离甲状腺激素(FT4)和促甲状腺激素(TSH)水平升高,临床高度怀疑RTH并进行基因检测。报告显示甲状腺激素受体β(THRβ)存在c.1313G>A杂合突变,导致第438号氨基酸由精氨酸变异为组氨酸(p.R438H),为错义突变,遗传情况未明。根据ACMG指南,这个变异初步判定为致病性变异。这种变异未见报道,被认为是新发变异。结论THRβ基因第8号外显子c.1313G>A突变可能是引起该先证者RTH的原因,该变异c.1313G>A位于THRβ的配体结合域,可能通过影响蛋白的三维结构及活性,从而影响THRβ的功能。Objective To assess clinical and genetic features in a patient with thyroid hormone resistance syndrome(RTH)and explore the pathogenic mechanism.Methods The clinical data of the proband was collected.The genomic DNA was extracted from peripheral blood samples of the patients.The pathogenic variant was identified using whole-exome sequencing and confirmed by Sanger sequencing.Then the function of the mutation sites was detected by bioinformatics.Results The patient presented with chest distress,palpitation,and persistent atrial fibrillation,along with elevated levels of serum free triiodothyronine(FT3),free thyroxine(FT4),and thyroid stimulating hormone(TSH),which suggested RTH clinically.The genetic analysis identified a heterozygous mutant of THRβ(c.1313G>A)gene at exon 8,which was a missense mutation causing the substitution of arginine to histidine at 438 position of the protein(p.R438H).Its inheritance pattern was unknown.This mutation was considered as a new one that had not been reported.Conclusion A novel pathogenic THRβgene mutation was found in the patient with RTH,which might be the cause of this disease.This variant c.1313G>A is located in the ligand binding domain of THRβ,which might result in low protein activity.

关 键 词：甲状腺激素抵抗综合征 甲状腺激素受体β 杂合突变 

分 类 号：R581[医药卫生—内分泌]