青岛地区21-羟化酶缺乏症基因型与临床表型相关性研究

Genotype-phenotype correlations in patients with 21-hydroxylase deficiency in Qingdao area

目的探讨青岛地区21-羟化酶缺乏症CYP21A2基因变异特点,以及基因型与临床表型的相关性。方法回顾性分析2010年1月至2021年12月青岛市新生儿疾病筛查中心确诊的21-羟化酶缺乏症患儿临床资料,根据患儿临床表现及实验室检查结果分为失盐型、单纯男性化型、非经典型。采用Sanger测序和多重连接探针扩增技术检测CYP21A2基因变异,按残余酶活性分为重度变异组、中度变异组、轻度变异组、未知变异组,分析基因型与临床表型的关系。结果(1)青岛地区12年间共确诊先天性肾上腺皮质增生症(congenital adrenal hyperplasia,CAH)患儿57例,发病率1/20877,经基因检测确诊的32例21-羟化酶缺乏症患儿中,失盐型19例,单纯男性化型8例,非经典型5例。(2)32例患儿共检出67个、14种等位基因变异,出现频率较高的是c.293-13A/C>G、c.518T>A、大的基因缺失/转换变异。(3)11例重度变异组中失盐型10例,12例中度变异组中单纯男性化8例,6例轻度变异组中非经典型4例。(4)骨龄提前或落后、性早熟、矮身材的患儿以c.293-13A/C>G、c.518T>A、大的基因缺失/转换变异、c.-113G>A基因变异为主。结论c.293-13A/C>G、c.518T>A、大的基因缺失/转换变异为青岛地区21-羟化酶缺乏症患儿的常见基因变异。基因检测可以预测临床表型,为治疗、预后提供依据,对产前诊断、遗传咨询具有重要意义。

Objective To study CYP21A2 mutation profiles and genotype-phenotype correlations in patients with 21-hydroxylase deficiency(21-OHD)in Qingdao area.Methods From January 2010 to December 2021,clinical data of infants with 21-OHD diagnosed in Qingdao Neonatal Disease Screening Center were retrospectively analyzed.According to clinical manifestations and laboratory tests,the infants were assigned into salt wasting forms(SW),simple virilization forms(SV)and non-classic forms(NC).CYP21A2 gene mutations were detected using Sanger sequencing and multiple ligated probe amplification(MLPA)methods.Alleles were grouped as severe,moderate,mild and unknown based on residual enzyme activity and genotype-phenotype correlations were analyzed.Results(1)A total of 57 cases of congenital adrenal hyperplasia(CAH)were diagnosed during the past 12 years(incidence rate 1/20877),including 32 cases of 21-OHD.19 cases of 21-OHD were SW,8 SV and 5 NC.(2)A total of 67 alleles with 14 types of gene mutations were detected.c.293-13A/C>G,c.518T>A and large gene deletion/conversion were the most common mutations.(3)10 cases of SW were in the severe group(11 cases),8 cases of SV were in the moderate group(12 cases)and 4 cases of NC were in the mild group(6 cases).(4)c.293-13A/C>G,c.518T>A,c.-113G>A and large gene deletion/conversion mutations were common in patients with premature or delayed bone age,precocious puberty and short stature.Conclusions c.293-13A/C>G,c.518T>A and large gene deletion/conversion mutation were common in infants with 21-OHD in Qingdao area.Genetic testing can predict clinical phenotypes for better treatment and prognosis and is helpful for prenatal diagnosis and genetic counseling.