摘要
目的经典型21-羟化酶缺乏症(21-OHD)由CYP21A2基因突变引起,不同地区CYP21A2的突变频率不同,基因型-表型相关性也不完全一致。文中旨在探讨湖北地区经典型21-OHD患儿基因型与临床分型关系,通过基因型预测临床分型,为新生儿筛查阳性患儿的诊疗提供帮助。方法回顾性分析2010年8月至2019年3月武汉儿童医院遗传代谢内分泌科64例确诊为经典型21-OHD的患者。记录经典型21-OHD患者的具体临床分型(失盐型、单纯男性化型)、基因验证结果。采用二代测序联合多重链接探针扩增技术检测先证者及父母的基因型。根据突变从重到轻分为:极重度突变组(n=15)、重度突变组(n=23)、中度突变组(n=23)、未知突变组(n=3)。观察不同基因组与临床分型的相关性。结果 64例患儿中,失盐型40例(62.5%),单纯男性化型24例(37.5%);最常见的3种突变为I2G(28.8%)、p.I173N(21.6%)、Del(20.9%)。失盐型最常见的突变位点为I2G(39.8%)、Del(25.0%)、p.R357W(15.9%)、p.Q319X(8.0%)。单纯男性化型最常见的突变位点为p.I173N(51.0%)、Del(13.7%)、I2G(9.8%)、p.R484P(9.8%)。极重度突变组对失盐型的阳性预测率为86.7%(13/15),重度突变组对失盐型的阳性预测率为100%(22/22),中度突变组对单纯男性化型的阳性预测率为87.0%(20/23)。极重度突变组、重度突变组、中度突变组基因型与经典型21-OHD临床分型存在显著正相关(rs=0.691,P=0.00)。单纯男性化型患儿占比随基因突变对应的残留21-OHD活性增加而逐渐增多。结论 21-OHD患儿基因型为极重度和重度突变时倾向于失盐型;中度突变时倾向于单纯男性化型。基因型可以预测临床分型,为21-OHD患儿的诊疗提供了依据。
Objective Classical 21-hydroxylase deficiency is caused by mutations in the CYP21A2 gene.The mutation frequency of CYP21A2 is different in different regions,and the genotype-phenotype correlation is not completely consistent.The relationship between genotype and clinical typing of children with OHD,predicting the clinical typing by genotype,and providing help for the diagnosis and treatment of children with positive newborn screening.Methods A retrospective analysis was performed,including 64 patients diagnosed with classic 21-OHD in the Department of Genetics,Metabolism,and Endocrinology,Wuhan Children's Hospital from August 2010 to March 2019.The clinical phenotype was evaluated and the genes of proband and parents were detected by secondgeneration sequencing and multiple link probe amplification.According to Speiser's in vitro study of 21-hydroxylase activity at common mutation sites,the genotypes were divided into extreme serious mutation group,serious mutation group,and moderate mutation group from heavy to light,to observe the correlation between different groups and clinical types.Results Of the 64 children,40(62.5%)were with salt-loss type and 24 cases(37.5%)with simple virilization type.The four most common mutations were I2G(28.8%),p.I173N(21.6%),Del(20.9%),and p.R357W(12.2%).The positive prediction rate of extreme serious mutation group(salt-wasting type),serious mutation group(salt-wasting type),and moderate mutation group(simple virilization type)was 86.7%,100%,and 87.0%,respectively.The overall genotype-phenotype correlation was 91.8%,and the correlation coefficient between phenotype severity and genotype rs was 0.691(P<0.05).Conclusion When the genotype is group extreme serious and serious mutation group,the salt-wasting type should mainly be considered.If it is a moderate mutation group,the simple virilization type should be considered.Genotypes have high reliability in predicting phenotype of 21-hydroxylase deficiency,which can provide molecular diagnosis and treatment basis for specific clinical classification of newborn screening 21-hydroxylase deficiency children in Hubei Province.
作者
兰天
姚辉
LAN Tian;YAO Hui(Department of Genetic Metabolism and Endocrinology,Wuhan Children's Hospital,Huazhong University of Science and Technology,Wuhan 430016,Hubei,China)
出处
《医学研究生学报》
CAS
北大核心
2020年第10期1056-1060,共5页
Journal of Medical Postgraduates
基金
湖北省自然科学基金(2015CKC909)。
