GATA3基因变异导致甲状旁腺功能减退症患者的临床特征和分子机制

Clinical characteristics and molecular mechanisms of hypoparathyroidism related to GATA3 gene mutation

目的分析GATA3基因变异导致甲状旁腺功能减退症(hypoparathyroidism,HP)患者的临床特点及分子机制。方法在1975年至2020年间于北京协和医院内分泌科随诊并行靶向基因捕获联合二代测序的198例未成年人(≤18岁)起病的非手术性HP患者中筛查到5例GATA3基因致病/可疑致病性变异,回顾性收集分析其临床资料,并对基因检测结果进行生物信息学分析。结果5例患者HP的起病年龄为0.5(0.1,1.3)岁,发病至诊断为HP和甲状旁腺功能减退-耳聋-肾发育不良(hypoparathyroidism-deafness-renal dysplasia,HDR)综合征的时间分别为(7.0±5.2)年和(15.0±5.4)年。临床表现为手足搐搦伴癫痫样发作、颅内钙化各5例,白内障1例,听力减退4例,肾脏畸形或缺如2例。治疗前血钙和血甲状旁腺激素(PTH)分别为(1.65±0.31)mmol/L和(4.64±2.63)ng/L。5例患者GATA3基因的杂合变异,分别引起无义突变、移码突变和剪接位点突变,经Clin Var数据库预测及美国医学遗传学和基因组学学会(ACMG)分级为致病性或可能致病性变异。结论对于儿童期起病的HP,应注意遗传性疾病的筛查,其中对于合并听力下降或肾脏发育异常的患者要考虑到HDR综合征的可能,有条件时应筛查GATA3基因以明确诊断。

Objective To analyze the clinical characteristics and molecular mechanisms of 5 cases of hypoparathyroidism caused by GATA3 gene mutation.Methods A total of 5 childhood-onset hypoparathyroidism patients with GATA3 mutation were identified from 198 hypoparathyroidism(aged≤18 years)from 1975 to 2021 in Peking Union Medical College Hospital.Clinical data and biochemical indices of the 5 patients were collected and analyzed retrospectively.Genetic screening was conducted by targeted next-generation sequencing(T-NGS),and bioinformatics analysis was performed to analyze the underline mechanisms.Results The medium onset age of hypoparathyroidism of the 5 patients was 0.5(0.1,1.3)years old,and the time duration from onset to confirmed diagnosis of hypoparathyroidism and hypoparathyroidism-deafness-renal dysplasia syndrome was(7.0±5.2)years and(15.0±5.4)years,respectively.The clinical manifestations included carpopedal spasm accompanied by seizures(5 cases),basal ganglia calcification(5 cases),cataract(1 case),deafness(4 cases),and renal malformations or absence(2 cases).The blood calcium and blood parathormone(PTH)before treatment was(1.65±0.31)mmol/L and(4.64±2.63)ng/L,respectively.The 5 patients carried different heterozygous mutations in GATA3 gene,which caused nonsense mutations,frameshift mutations and splice site mutations,respectively.All the GATA3 gene mutations of the 5 patients are classified as pathogenic or likely pathogenic by the Clin Var database and American College of Medical Genetics and Genomics(ACMG).Conclusions Attention should be paid to genetic diseases in patients with childhood-onset hypoparathyroidism.The possibility of hypoparathyroidism-deafness-renal dysplasia syndrome should be considered in hypoparathyroidism patients with hearing loss or renal dysplasia.GATA3 gene screening is highly recommended for the confirmation of the diagnosis.