2例MYH3基因变异致远端关节挛缩综合征患儿临床特征和基因检测结果分析

doi:10.3969/j.issn.1673-8640.2023.02.005

检验医学 ›› 2023, Vol. 38 ›› Issue (2): 124-129.DOI: 10.3969/j.issn.1673-8640.2023.02.005

• 基因组技术与罕见病诊治专题 • 上一篇下一篇

2例MYH3基因变异致远端关节挛缩综合征患儿临床特征和基因检测结果分析

程欢欢, 赵钰玮()

安徽省儿童医院新生儿科，安徽合肥 230022

收稿日期:2022-09-02 修回日期:2022-12-15 出版日期:2023-02-28 发布日期:2023-04-17
通讯作者: 赵钰玮，E-mail：zyw3257@sina.com。
作者简介:程欢欢，女，1987年生，硕士，主治医师，主要从事新生儿遗传缺陷分子诊断工作。
基金资助:
中央财政省级临床重点专科建设项目(Z155080000004)

Clinical characteristic and genetic test analysis of 2 neonates with congenital distal arthrogryposis caused by MYH3 mutation

CHENG Huanhuan, ZHAO Yuwei()

Department of Neonatology，Anhui Children's Hospital，Hefei 230022，Anhui，China

Received:2022-09-02 Revised:2022-12-15 Online:2023-02-28 Published:2023-04-17

摘要/Abstract

摘要：

目的分析2例远端关节挛缩综合征（DA）患儿的临床特征和基因检测结果，以提高临床对该病的认识。方法回顾分析2例DA患儿的临床资料，并对患儿及其父母进行全外显子组家系测序（Trio-WES）。对发现的可疑变异进行生物信息学分析和Sanger测序验证，构建变异型蛋白空间结构，分析其生物危害性。结果 2例DA患儿均表现为严重的手足关节挛缩。Trio-WES结果提示2例患儿MYH3基因均发生变异，患儿1为c.1106A>G（p. Gln369Arg），患儿2为c.3059C>A（p.Ser1020Tyr），2例患儿的父母该位点均为野生型。c.1106A>G（p.Gln369Arg）在dbSNP数据库、ExAC数据库、千人基因组数据库、gnomAD数据库中未被收录。c.3059C>A（p.Ser1020Tyr）仅被gnomAD数据库收录，分布频率为0.000 1；在HGMD数据库和PubMed数据库中未见报道。c.1106A>G（p.Gln369Arg）和c.3059C>A（p.Ser1020Tyr）美国医学遗传学和基因组学学会（ACMG）指南评级均为可能致病。2个变异均可能导致蛋白局部结构稳定性降低，影响蛋白功能。结论 2例由MYH3基因变异导致的DA患儿均表现出关节挛缩特征。发现了2个MYH3基因的新发变异，扩展了中国人群MYH3基因变异谱和DA表型谱。

关键词: MYH3基因, 全外显子组家系测序, 远端关节挛缩综合征

Abstract:

Objective To analyze the clinical characteristics and genetic test analysis results of 2 neonates with distal arthrogryposis （DA），and to improve the understanding of DA. Methods The clinical data of 2 neonates with DA were analyzed retrospectively，and the trio-whole-exome sequencing （Trio-WES） of the 2 neonates and their parents were sequenced. Bioinformatics prediction analysis and Sanger sequencing verification were carried out for the suspicious mutations found，and the spatial structure of mutation protein was constructed to analyze its biological hazard. Results The 2 neonates with DA showed severe hand foot joint contracture. The results of Trio-WES indicated that MYH3 mutation occurred in the 2 neonates. Case 1 was c.1106A>G（ p. Gln369Arg），and Case 2 was c.3059C>A（p. Ser1020Tyr），and the parents of 2 neonates were wild-type. The c.1106A>G（ p.Gln369Arg），which was not included in dbSNP，ExAC，1000 Genomes and gnomeAD databases. The c.3059C>A（ p.Ser1020Tyr） was only distributed in the gnomeAD database with a frequency of 0.0001. It had not been reported in HGMD database and Pubmed database. Both c.1106A>G（ p.Gln369Arg） and c.3059C>A（p.Ser1020Tyr） were rated as possibly pathogenic according to the guidelines of American College of Medical Genetics and Genomics （ACMG）. Both of the 2 mutations may lead to a decrease in the stability of protein local structure and affect the function of protein. Conclusions The 2 neonates with DA caused by MYH3 mutation show the characteristics of joint contracture. Two mutations of MYH3 have been found，which expand the variation spectrum of MYH3 and DA phenotype spectrum of Chinese population.

Key words: MYH3, Trio-whole-exome sequencing, Distal arthrogryposis

中图分类号:

R446.1

程欢欢, 赵钰玮. 2例MYH3基因变异致远端关节挛缩综合征患儿临床特征和基因检测结果分析[J]. 检验医学, 2023, 38(2): 124-129.

CHENG Huanhuan, ZHAO Yuwei. Clinical characteristic and genetic test analysis of 2 neonates with congenital distal arthrogryposis caused by MYH3 mutation[J]. Laboratory Medicine, 2023, 38(2): 124-129.

图/表 4

图1 2例患儿影像学检查结果注：（a）患儿1心脏彩色多普勒超声检查提示房间隔缺损；（b）患儿1心脏彩色多普勒超声检查提示动脉导管未闭；（c）患儿1髋关节超声检查提示左侧髋关节GrafⅠb型；（d）患儿1髋关节超声检查提示右侧髋关节GrafⅠb型；（e）患儿2髋关节超声检查提示左髋关节GrafⅡc型；（f）患儿2髋关节超声检查提示右髋关节GrafⅡa型；（g）患儿2四肢长骨X线检查提示左侧桡骨近端内侧缘骨性凸起；（h）患儿2四肢长骨X线检查提示右侧桡骨近端内侧缘骨性凸起。

图2 Sanger测序结果注：（a）患儿1的MYH3基因发生杂合变异[c.1106A>G（p. Gln369Arg）]，父母该位点均为野生型；（b）患儿2的MYH3基因发生杂合变异[c.3059C>A（p.Ser1020Tyr）]，父母该位点为野生型。

图3 变异型MYH3蛋白Gln369Arg结构变化注：（a）MYH3蛋白结构示意图；（b）野生型Gln369结构（箭头所指）；（c）变异型Gln369Arg结构；Gln369位于Loop结构上，当Gln369Arg变异发生后，与位于另一个Loop结构上的Asn445残基形成氢键（红色方框），因此变异可能导致局部结构刚性增强。

图4 变异型MYH3蛋白Ser1020Tyr结构变化注：（a）MYH3蛋白结构示意图；（b）野生型Ser1020结构（箭头所指）；（c）变异型Ser1020Tyr结构；Ser1020Tyr发生变异后，因Tyr1020的苯环结构而与周围氨基酸形成疏水作用，同时与Tyr622残基形成氢键（红色方框），使变异可能导致局部结构刚性增强。

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2例MYH3基因变异致远端关节挛缩综合征患儿临床特征和基因检测结果分析

Clinical characteristic and genetic test analysis of 2 neonates with congenital distal arthrogryposis caused by MYH3 mutation

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