重庆部分地区苯丙氨酸羟化酶缺乏症患儿基因突变分析

王冬娟; 张娟; 刘浩; 杨静; 万科星; 袁召建; 余朝文; 张大勇; 刘姗; 邹琳

doi:10.16016/j.1000-5404.202010198

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重庆部分地区苯丙氨酸羟化酶缺乏症患儿基因突变分析

临床医学 | 更新时间：2021-08-02

- 重庆部分地区苯丙氨酸羟化酶缺乏症患儿基因突变分析
- Gene mutations in children with phenylalanine hydroxylase deficiency: an analysis of 45 cases in some regions of Chongqing
- 陆军军医大学学报 2021年43卷第9期页码：876-882
- 作者机构：
  
  重庆医科大学附属儿童医院临床分子医学中心，国家儿童健康与疾病临床医学研究中心，儿童发育疾病研究教育部重点实验室，儿科学重庆市重点实验室,重庆
- 作者简介：
- 基金信息：
- DOI：10.16016/j.1000-5404.202010198
  中图分类号： R394.5;R725.893;R195.4
- 纸质出版日期：2021，
  
  网络出版日期：2021-5-15，
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[1]王冬娟,张娟,刘浩,等.重庆部分地区苯丙氨酸羟化酶缺乏症患儿基因突变分析[J].陆军军医大学学报(原第三军医大学学报),2021,43(09):876-882.WANG Dongjuan,ZHANG Juan,LIU Hao,et al.Gene mutations in children with phenylalanine hydroxylase deficiency: an analysis of 45 cases in some regions of Chongqing[J].J Amry Med Univ (J Third Mil Med Univ),2021,43(09):876-882.

WANG Dongjuan, ZHANG Juan, LIU Hao, et al. Gene mutations in children with phenylalanine hydroxylase deficiency: an analysis of 45 cases in some regions of Chongqing[J]. Journal of Army Medical University, 2021,43(9):876-882.
[1]王冬娟,张娟,刘浩,等.重庆部分地区苯丙氨酸羟化酶缺乏症患儿基因突变分析[J].陆军军医大学学报(原第三军医大学学报),2021,43(09):876-882.WANG Dongjuan,ZHANG Juan,LIU Hao,et al.Gene mutations in children with phenylalanine hydroxylase deficiency: an analysis of 45 cases in some regions of Chongqing[J].J Amry Med Univ (J Third Mil Med Univ),2021,43(09):876-882. DOI： 10.16016/j.1000-5404.202010198.

WANG Dongjuan, ZHANG Juan, LIU Hao, et al. Gene mutations in children with phenylalanine hydroxylase deficiency: an analysis of 45 cases in some regions of Chongqing[J]. Journal of Army Medical University, 2021,43(9):876-882. DOI： 10.16016/j.1000-5404.202010198.

摘要

目的探讨重庆部分区域苯丙氨酸羟化酶（phenylalanine hydroxylase，PAH）缺乏症基因突变频率和特征，为PAH缺乏症的诊断及治疗提供依据。方法回顾性分析2014年1月1日至2020年10月25日在重庆医科大学附属儿童医院确诊的45例PAH缺乏症患儿，将苯丙氨酸羟化酶缺乏症分型为经典型苯丙酮尿症（phenylketonuria，PKU）、轻度PKU及轻度高苯丙氨酸血症（hyperphenylalaninemia，HPA），分析其二代高通量测序及多重连接依赖探针扩增技术检测的PAH基因突变情况以及Sanger测序技术对其父母相应变异位点的验证结果。结果 ①45例高苯丙氨酸血症患者中43例均检出2个变异位点（40例为复合杂合突变，3例为纯合突变），且所检测突变位点均来自父母；另外2例为杂合突变，仅检测到1个变异位点。②45例PAH缺乏症患者共检出34种突变，主要以错义突变（52.9%）为主，c.728G＞A突变频率最高（15.9%，14/88），其次为c.158G＞A（11.4%，10/88）、c.1197A＞T（9.1%，8/88）及c.721C＞T（9.1%，8/88）。高频突变的区域在第7外显子，包含4种突变，26个变异位点（29.5%）。③13例经典型PKU患者检测到11种PAH基因突变，其中突变频率最高的为c.728G＞A（8/25，32%）；8例轻度PKU患者检测到9种PAH基因突变，c.728G＞A（3/15，20%）突变频率最高；24例轻度HPA患者共检出24种PAH基因突变，其中c.158G＞A（10/48，20.8%）突变频率最高。结论重庆市PAH缺乏症患者PAH基因突变以复合杂合为主，主要变异类型为错义突变，具有明显的热点突变（c.728G＞A、c.158G＞A、c.721C＞T及c.1197A＞T）。

Abstract

ObjectiveTo explore the gene mutation frequency and characteristics of phenylalanine hydroxylase (PAH) in PAH deficiency children in some regions of Chongqing in order to provide scientific reference for the diagnosis and treatment of the disease. MethodsA retrospective analysis was conducted on 45 children with PAH deficiency who were diagnosed in our hospital from January 1

2014 to October 25

2020. They was assigned into classic phenylketonuria (PKU)

mild PKU and mild hyperphenylalaninemia (HPA). We analyzed the mutations of PAH gene by second-generation high-throughput sequencing and multiplex ligase probe dependent amplification (MLPA) technique

and the results were verified by the detection of corresponding mutation sites of their parents by Sanger sequencing. Results① There were 2 mutation sites in 43 cases

including 40 cases of compound heterozygous mutation and 3 cases of homozygous mutation. All mutations were detected in the corresponding mutation sites of their parents. The left 2 cases had heterozygous mutations

and had only 1 mutation site. ② There were 34 types of mutations detected in 45 patients with PAH deficiency. Missense mutation was the main mutation type (52.9%). The mutation frequency of c.728G>A was the highest (15.9%

14/88)

followed by c.158G>A (11.4%

10/ 88)

c.1197A>T (9.1%

8/88)

and c.721C＞T (9.1%

8/88). The region of high frequency mutation was in exon 7

which contained 4 mutations and 26 mutations sites (29.5%). ③ There were 11 PAH gene mutations in 13 patients with classic PKU. The mutation frequency of c.728G> A (8/25

32%) was the highest. There were 9 PAH gene mutations in 8 patients with mild PKU. The mutation frequency of c.728G>A (3/15

20%) was the highest. There were 24 PAH gene mutations in 24 patients with mild HPA. The mutation frequency of c.158G>A (10/48

20.8%). ConclusionThe mutations in children with PAH deficiency in some regions of Chongqing are mainly compound heterozygosity. Missense mutation is the main type

with obvious hot spot mutations (c.728G>A

c.158G>A

c.721C＞T and c.1197A>T).

关键词

高苯丙氨酸血症新生儿疾病筛查苯丙氨酸羟化酶基因突变

Keywords

hyperphenylalaninemianeonatal disease screeningphenylalanine hydroxylasegene mutation

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