新疆部分地市苯丙酮尿症患儿苯丙氨酸羟化酶基因变异特点分析

Genetic profiles of phenylalanine hydroxylase gene mutations in neonates with phenylketonuria in Xinjiang

目的分析新疆部分地市苯丙酮尿症(phenylketonuria,PKU)患儿苯丙氨酸羟化酶(phenylalanine hydroxylase,PAH)基因变异的特点。方法选择2015年1月至2021年12月在新疆乌鲁木齐市妇幼保健院管理辖区(包括乌鲁木齐市、吐鲁番市、塔城地区、昌吉州)出生并经基因诊断确诊PKU的新生儿进行回顾性研究,分析不同民族的基因变异特点,并与中国中部地区、西北地区、北方地区PKU患儿基因变异构成进行比较。结果共纳入131例PKU患儿,其中汉族82例、回族25例、维吾尔族20例、哈萨克族2例、锡伯族及蒙古族各1例,汉族、回族、维吾尔族分别检出46种、20种、14种致病变异位点,检出率分别为95.1%(156/164)、66.0%(33/50)、60.0%(24/40),均以错义变异为主。各民族PAH基因致病变异位点主要集中在外显子2、3、6、7、11。回族PKU患儿PAH基因最常见的致病变异位点依次是c.158G>A(18.2%)、c.728G>A(18.2%)、c.898G>T(9.1%),维吾尔族PKU患儿PAH基因最常见的致病变异位点依次是c.158G>A(33.3%)、c.355C>T(12.5%)、c.1068C>A(8.3%)。c.898G>T、c.355C>T可能分别是新疆回族及维吾尔族独有的变异类型。本研究发现PAH基因1个新发变异c.828G>C(p.M276I),位于7号外显子。与中国北方、中部及西北地区相比,新疆部分地市PKU患儿c.158G>A基因变异检出率更高,c.728G>A基因变异检出率更低,差异均有统计学意义(P<0.05)。结论新疆部分地市PKU患儿PAH基因主要类型为错义变异,PAH基因变异构成与中国西北地区和北方地区相似,但变异热点存在较大差异。

Objective To study the genetic profiles of phenylalanine hydroxylase(PAH)gene mutations in neonates with phenylketonuria(PKU)in Xinjiang.Methods From January 2015 to December 2021,neonates born and genetically diagnosed with PKU in our region were retrospectively included.The genetic profiles of different ethnic groups were analyzed and compared with PKU patients from central,northwest and northern regions of China.Results A total of 131 neonates with PKU were enrolled,including 82 Han,25 Hui and 20 Uyghur patients,4 cases of other ethnic groups.46,20 and 14 types of pathogenic variants were detected in each ethnic group with detection rates of 95.1%(156/164),66.0%(33/50),and 60.0%(24/40),respectively.The variants were mainly missense mutations and located in exons 2,3,6,7 and 11.The most common loci in Hui patients were c.158G>A(18.2%),c.728G>A(18.2%)and c.898G>T(9.1%).The most common loci in Uyghur patients were c.158G>A(33.3%),c.355C>T(12.5%)and c.1068C>A(8.3%).c.898G>T might be most unique in Hui patients and c.355C>T most unique in Uyghur patients in Xinjiang.A novel variant of PAH gene,c.828G>C(p.M276I)in exon 7 was identified.Compared with northern,central and northwestern regions of China,PKU patients in Xinjiang had significantly higher incidence of c.158G>A mutation and lower incidence of c.728G>A mutation(P<0.05).Conclusions Missense mutations of PAH gene are common in some regions of Xinjiang.The compositions of PAH gene variations are similar to northwest and northern China with significant differences in hotspots of mutations.