扬州地区高苯丙氨酸血症筛查及致病基因特征研究

Screening for hyperphenylalaninemia and pathogenic gene characteristics in Yangzhou area

目的探讨扬州地区新生儿高苯丙氨酸血症(HPA)发生情况,分析本地区HPA基因突变特征。方法采用茚三酮荧光法或者串联质谱检测法对2013年1月—2022年12月扬州地区出生的285549例新生儿进行HPA筛查。筛查阳性者进行尿蝶呤分析、红细胞二氢喋啶还原酶活性测定和基因诊断。结果确诊HPA 29例,其中四氢生物蝶呤(BH4)缺乏症3例,苯丙氨酸羟化酶(PAH)缺乏症26例。扬州地区HPA总体发病率为1/9847,PAH缺乏症发病率为1/10983,略高于全国平均水平,低于江苏省其他地区。其中,经典型苯丙酮尿症(PKU)13例(44.83%),轻度PKU 7例(24.14%),轻度HPA 6例(20.69%)。16例患儿PAH基因突变,全部为复合杂合突变,其中1例发现3位点突变。PAH基因以错义突变为主,主要集中于外显子7,其次是外显子6,E7 c.728G>A(21.21%)突变频率最高。3例BH4缺乏症全部检出PTS基因,1例为纯合突变,2例为复合杂合突变。E5 c.259C>T是扬州地区PTS高频突变基因。结论扬州地区HPA具有一定发病率,且以经典型PKU为主。本研究明确了扬州地区PAH、PTS基因突变特征,丰富了HPA基因数据库。

Objective To investigate the incidence of neonatal hyperphenylalaninemia(HPA)and analyze the characteristics of HPA gene mutations in the Yangzhou area.Methods From January 2013 to December 2022,285,549 newborns in Yangzhou were screened for HPA using either the ninhydrin fluorescence method or tandem mass spectrometry.Urinary pterin analysis,erythrocyte dihydrobiopterin reductase activity measurement and genetic diagnosis were performed to screen positive individuals.Results A total of 29 cases were confirmed as HPA,including 3 cases of tetrahydrobiopterin(BH 4)deficiency and 26 cases of phenylalanine hydroxylase(PAH)deficiency.The overall incidence of HPA in Yangzhou was 1/9,847,with the incidence of PAH deficiency being 1/10,983,which were slightly higher than the national average but lower than other regions in Jiangsu Province.Among the cases,13(44.83%)were classic phenylketonuria(PKU),7(24.14%)were mild PKU,and 6(20.69%)were mild HPA.Sixteen patients with PAH gene mutations were all compound heterozygotes,with one case exhibiting three-site mutations.PAH gene mutations were predominantly missense mutations,primarily concentrated in exon 7,followed by exon 6,with E7 c.728G>A(21.21%)being the most frequent mutation.Three cases of BH 4 deficiency were detected with PTS gene mutations,including 1 homozygous mutation and 2 compound heterozygous mutations.E5 c.259C>T was the high-frequency PTS mutation gene in Yangzhou.Conclusion HPA has a certain incidence in Yangzhou,with classic PKU being the predominant type.This study clarified the characteristics of PAH and PTS gene mutations in Yangzhou,enriching the HPA gene database.