摘要
目的:了解浙江省新生儿先天性甲状腺功能减退症(CH)及高苯丙氨酸血症(HPA)的筛查及发病情况。方法:收集1999年9月至2022年12月浙江省新生儿疾病筛查中心11 922 318名新生儿血促甲状腺素(TSH)及苯丙氨酸(Phe)检测的资料。其中,血TSH浓度采用荧光法检测,血Phe浓度采用荧光法或串联质谱法检测。TSH在9μIU/mL及以上的新生儿为CH筛查阳性,血Phe浓度超过120μmol/L和(或)血Phe与酪氨酸(Tyr)比值大于2.0为HPA筛查阳性,召回复查。采用高通量测序和MassARRAY技术检测基因变异。结果:1999—2022年共筛查新生儿11 922 318名,总筛查率为89.41%,筛查率由1999年6.46%提升至2022年的100.00%。检出CH患儿8924例,患病率为1/1336,检出HPA患儿563例,患病率为1/21 176,其中508例为经典型苯丙酮尿症(cPKU),55例为四氢生物蝶呤缺乏症(BH4D)。97例CH患儿完善基因检测,检出9种CH相关基因,双氧化酶2(DUOX2)基因检出频率最高(69.0%),其中c. 3329G>A(p. R1110Q)(18.2%)和c.1588A>T(p.K530X)(17.3%)为热点突变。250例cPKU患者中检出81种苯丙氨酸羟化酶(PAH)基因变异,其中c728G>A(p.R243Q)(24.4%)和c.721C>T(p.R241C)(15.0%)为热点突变,7种为新发变异:c.107C>A(p.S36*)、c.137G>T(p.G46V)、c.148A>G(p.K50E)、c.285C>T(p.I95I)、c.843-10del TTCC、exon4-7del和c.1066-2A>G。36例BH4D患者中检出12种6-丙酮酰四氢蝶呤合成酶(PTS)基因变异,热点突变为c.259C>T(p.P87S)(31.9%)。结论:浙江省新生儿筛查率逐年升高,CH发病率明显增高,HPA发病率与全国平均水平接近。DUOX2基因变异为CH患儿最常见基因变异,c728G>A(p.R243Q)为cPKU患者的热点突变,c.259C>T(p.P87S)为BH4D患者的热点突变。
Objective:To analyze the results of neonatal screening for congenital hypothyroidism(CH)and hyperphenylalaninemia(HPA)in Zhejiang province from 1999 to 2022.Methods:A total of 11922318 newborns were screened from September 1999 and December 2022 in Zhejiang province.The blood thyroid stimulating hormone(TSH)levels were measured by a fluorescence method and blood phenylalanine(Phe)levels were measured by fluorescence method or tandem mass spectrometry.TSH≥9μIU/mL was considered positive for CH,while Phe>120μmol/L and/or Phe/Tyr ratio>2.0 were considered positive for HPA.The positive newborns in screening were recalled,and the gene variations were detected by high-throughput sequencing and MassARRAY tests.Results:The overall neonatal screening rate during 1999—2022 was 89.41%(11922318/13333929)and the screening rate was increased from 6.46%in 1999 to 100.0%in 2022.A total of 8924 cases of CH were diagnosed among screened newborns with an incidence rate of 1/1336.A total of 563 cases of HPA were diagnosed,including 508 cases of classic phenylketonuria(cPKU)and 55 cases of tetrahydrobiopterin deficiency(BH4D),with an incidence rate of 1/21176.Ninety-seven out of 8924 cases of CH underwent genetic analysis.Gene mutations were detected in 9 CH related genes,the highest frequency mutations were found in DUOX2 gene(69.0%)with c.3329G>A(p.R1110Q)(18.2%)and c.1588A>T(p.K530X)(17.3%)as the hotspot mutations.There were 81 PAH gene variants detected in a total of 250 cases of cPKU,and c728G>A(p.R243Q)(24.4%),c.721C>T(p.R241C)(15.0%)were the hotspot mutations.Meanwhile 7 novel variants in PAH gene were detected:c.107C>A(p.S36*),c.137G>T(p.G46V),c.148A>G(p.K50E),c.285C>T(p.I95I),c.843-10delTTCC,exon4-7del and c.1066-2A>G.There were 12 PTS gene variants detected in 36 cases of BH4D,and c.259C>T(p.P87S)(31.9%)was the hotspot mutation.Conclusions:The incident of CH has increased from 1999 to 2022 in Zhejiang province,and it is higher than that of national and global levels;while the incidence of HPA is similar to the national average.DUOX2 gene variation is the most common in CH patients;c.728G>A(p.R243Q)is the hotspot mutation in cPKU patients,while c.259C>T(p.P87S)is the hotspot mutation in BH4D patients.
作者
周朵
杨茹莱
黄新文
黄晓磊
杨昕
毛华庆
杨建滨
赵正言
ZHOU Duo;YANG Rulai;HUANG Xinwen;HUANG Xiaolei;YANG Xin;MAO Huaqing;YANG Jianbin;ZHAO Zhengyan(Department of Genetics and Metabolism,Children’s Hospital,Zhejiang University School of Medicine,National Clinical Research Center for Child Health,Hangzhou 310052,China)
出处
《浙江大学学报（医学版）》
CAS
CSCD
北大核心
2023年第6期683-692,共10页
Journal of Zhejiang University(Medical Sciences)
基金
国家重点研发计划(2022YFC2703401)。
