苯丙氨酸羟化酶缺乏症家系PAH基因新发突变分析

doi:10.3969/j.issn.1004-583X.2022.05.010

临床荟萃 ›› 2022, Vol. 37 ›› Issue (5): 441-446.doi: 10.3969/j.issn.1004-583X.2022.05.010

苯丙氨酸羟化酶缺乏症家系PAH基因新发突变分析

马翠霞^1a, 封露露^1a, 李丽欣^1a, 马倩倩², 李扬^1b, 封纪珍^1a()

1.石家庄市妇幼保健院 a.遗传科;b.产前诊断科,河北石家庄 050000
2.石家庄市妇产医院体检中心,河北石家庄 050000

收稿日期:2021-10-15 出版日期:2022-05-20 发布日期:2022-06-22
通讯作者: 封纪珍 E-mail:214674179@qq.com
基金资助:
河北省医学科学研究课题计划——新生儿四病筛查在出生缺陷预防中的应用和研究(20210689)

Analysis on de novo mutations in PAH genes of the family with phenylalanine hydroxylase deficiency

Ma Cuixia^1a, Feng Lulu^1a, Li Lixin^1a, Ma Qianqian², Li Yang^1b, Feng Jizhen^1a()

1a. Department of Heredity; 1b. Department of Prenatal Diagnosis, Shijiazhuang Maternity & Child Healthcare Hospital, Shijiazhuang 050000, China
2. Department of Medical Examination Center, Shijiazhuang Obstetrics and Gynecology Hospital, Shijiazhuang 050000, China

Received:2021-10-15 Online:2022-05-20 Published:2022-06-22
Contact: Feng Jizhen E-mail:214674179@qq.com

摘要/Abstract

摘要：

目的对一个苯丙氨酸羟化酶缺乏症(phenylalanine hydroxylase deficiency,PAHD)家系苯丙氨酸羟化酶(phenylalanine hydroxylase,PAH)基因进行突变位点检测和分析,探讨此家系发病原因。方法采用二代测序技术(next generation sequencing,NGS)和多重连接探针扩增技术(multiplex ligation-dependent probe amplification,MLPA)对先证者及其父母的静脉血进行PAH基因组测序和外显子缺失、重复分析。结果先证者找到1个错义突变和1个剪接缺失,分别为:第6外显子c.630T>G和第2外显子c.61-1G>A,这两个变异在人类基因突变数据库(Human Gene Mutation Database,HGMD)中未见报道,根据美国医学遗传学与基因组学学会(America College of Medical Genetics and Genomics, ACMG)指南判定为临床意义未明和疑似致病性变异;信息软件REVEL预测结果为有害和未知。采用MLPA对先证者进行外显子缺失、重复分析显示PAH基因外显子拷贝数未发现异常。结论 PAH基因6号外显子c.630T>G和2号外显子c.61-1G>A可能是该PAHD家系的致病突变。

关键词: 苯丙氨酸羟化酶, 苯丙酮尿症, 基因

Abstract:

Objective To investigate the pathogenesis of a family with phenylalanine hydroxylase deficiency (PAHD) by detecting and analyzing the mutation sites of phenylalanine hydroxylase (PAH) genes of the family. Methods PAH genome sequencing and exon deletion or duplication analysis were performed in the venous blood of probands and their parents by the next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA). Results The proband was found to have one missense mutation and one splice deletion, namely c.630t > G in Exon 6 and c.61-1G > A in Exon 2, respectively, which were not reported in Human Gene Mutation Database (HGMD), and were determined as clinically unknown and suspected pathogenic variants in America College of Medical Genetics and Genomics (ACMG) guidelines. The two mutations were predicted to be harmful and unknown in prediction results of information software REVEL, and no abnormal copy number of exon of PAH gene was found in the exon deletion and duplication analysis on the proband by using MLPA. Conclusion Exon 6 c.630T > G and exon 2 c.61-1G > A of PAH gene may be pathogenic mutations of PAHD in the family.

Key words: phenylalanine hydroxylase, phenylketonurias, genes

中图分类号:

R272.1

马翠霞, 封露露, 李丽欣, 马倩倩, 李扬, 封纪珍. 苯丙氨酸羟化酶缺乏症家系PAH基因新发突变分析[J]. 临床荟萃, 2022, 37(5): 441-446.

Ma Cuixia, Feng Lulu, Li Lixin, Ma Qianqian, Li Yang, Feng Jizhen. Analysis on de novo mutations in PAH genes of the family with phenylalanine hydroxylase deficiency[J]. Clinical Focus, 2022, 37(5): 441-446.

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链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2022.05.010

https://huicui.hebmu.edu.cn/CN/Y2022/V37/I5/441

图/表 6

图1 PAHD家系图

图2 PAHD患儿PAH基因外显子6中c.630T>G错义突变(箭头处为基因突变位置)

图3 PAHD患儿PAH基因外显子2中c.61-1G>A剪接突变(箭头处为基因突变位置)

图4 不同物种中PAH基因第210号编码的苯丙氨酸位点保守性

图5 PAH基因蛋白三维分子结构预测分析 a.野生型PAHp.F210L; b.突变型PAHp.F210L

图6 MLPA检测电泳峰图 a.对照样本;b.先证者

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苯丙氨酸羟化酶缺乏症家系PAH基因新发突变分析

Analysis on de novo mutations in PAH genes of the family with phenylalanine hydroxylase deficiency

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