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浙江大学学报（医学版）
浙江大学学报（医学版）  2020, Vol. 49 Issue (5): 574-580    DOI: 10.3785/j.issn.1008-9292.2020.10.04
专题报道     
联合氧化磷酸化缺陷症1型一家系临床表型及GFM1基因突变分析
沈亚平1(),严恺2,董旻岳2,杨茹莱1,黄新文1,*()
1. 浙江大学医学院附属儿童医院遗传与代谢科 国家儿童健康与疾病临床医学研究中心 国家儿童区域医疗中心, 浙江 杭州 310052
2. 浙江大学医学院附属妇产科医院生殖遗传科 生殖遗传教育部重点实验室, 浙江 杭州 310006
Analysis of GFM1 gene mutations in a family with combined oxidative phosphorylation deficiency 1
SHEN Yaping1(),YAN Kai2,DONG Minyue2,YANG Rulai1,HUANG Xinwen1,*()
1. Department of Genetics and Metabolism, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Regional Medical Centre for Children, Hangzhou 310052, China
2. Department of Reproductive Genetics, Women's Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Genetics, Ministry of Education, Hangzhou 310006, China
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摘要：

目的: 分析一个联合氧化磷酸化缺陷症1型家系的临床表型及遗传学特点，明确其遗传学病因。方法: 对先证者父母外周血DNA行全外显子组测序，对先证者（已故）干血斑标本、胎儿（先证者弟弟）羊水和先证者父母亲外周血行Sanger验证。结果: 全外显子组测序和Sanger测序显示，先证者及其弟弟均为GFM1基因c.688G>A（p.G230S）与c.1576C>T（p.R526X）复合杂合突变，其中c.1576C>T系首次报道。先证者及其弟弟出生后均出现代谢性酸中毒、高乳酸血症、肝功能异常、喂养困难、小头畸形、生长发育落后、癫痫等临床表现，均在婴儿早期死亡。结论: GFM1基因c.688G>A与c.1576C>T复合杂合突变是导致该家系联合氧化磷酸化缺陷症1型的遗传学原因。
关键词： 先天性遗传性新生儿疾病和畸形;  联合氧化磷酸化缺陷症1型;  GFM1基因;  代谢性酸中毒;  全外显子组测序    
Abstract:

Objective: To analyze the clinical phenotype and genetic characteristics of a family with combined oxidative phosphorylation deficiency 1 (COXPD-1). Methods: The whole exome sequencing was performed in parents of the proband; and the genetic defects were verified by Sanger sequencing technology in the dried blood spot of the proband, the amniotic fluid sample of the little brother of proband, and the peripheral blood of the parents. Results: Whole exome sequencing and Sanger validation showed compound heterozygous mutations of GFM1 gene c.688G>A(p.G230S) and c.1576C>T (p.R526X) in both the proband and her little brother, and the c.1576C>T of GFM1 variant was first reported. The two patients were died in early infancy, and presented with metabolic acidosis, high lactic acid, abnormal liver function, feeding difficulties, microcephaly, development retardation and epilepsy. Conclusion: GFM1 gene c.688G>A and c.1576C>T compound heterozygous mutations are the cause of this family of COXPD-1.
Key words: Congenital, hereditary, and neonatal diseases and abnormalities    Combined oxidative phosphorylation deficiency 1    GFM1 gene    Metabolic acidosis    Whole exome sequencing
收稿日期: 2020-05-12 出版日期: 2020-11-19
:  R394.3  
基金资助: 国家重点研发计划(2018YFC1002204)
通讯作者: 黄新文     E-mail: 6517066@zju.edu.cn;6305022@zju.edu.cn
作者简介: 沈亚平(1984-), 女, 硕士, 主管技师, 主要从事儿童遗传代谢病基因检测与分析; E-mail:6517066@zju.edu.cn; https://orcid.org/0000-0002-1600-2081
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引用本文:

沈亚平,严恺,董旻岳,杨茹莱,黄新文. 联合氧化磷酸化缺陷症1型一家系临床表型及GFM1基因突变分析[J]. 浙江大学学报（医学版）, 2020, 49(5): 574-580.

SHEN Yaping,YAN Kai,DONG Minyue,YANG Rulai,HUANG Xinwen. Analysis of GFM1 gene mutations in a family with combined oxidative phosphorylation deficiency 1. J Zhejiang Univ (Med Sci), 2020, 49(5): 574-580.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2020.10.04    或    http://www.zjujournals.com/med/CN/Y2020/V49/I5/574

图 1  联合氧化磷酸化缺陷症1型一家系GFM1基因测序结果
图 2  联合氧化磷酸化缺陷症1型患儿(先证者弟弟)头颅MRI图
图 3  联合氧化磷酸化缺陷症1型患儿(先证者弟弟)长程脑电监测图
编号 核苷酸改变 氨基酸改变 外显子位置 突变类型 等位基因突变个数 等位基因突变频率 参考文献序号
1 c.100C>T p.R34X 2 无义 1 0.016 18
2 c.130_137delGAAAAAATinsAAAAAAAA p.E44_I46delinsKKK 2 插入缺失 4 0.065 12
3 c.139C>T p.R47X 2 无义 1 0.016 8
4 c.170C>A p.S57Y 2 错义 1 0.016 15
5 c.238A>G p.K80E 3 错义 1 0.016 17
6 c.248A>T p.D83V 3 错义 1 0.016 18
7 c.521A>G p.N174S) 4 错义 4 0.065 6
8 c.539delG p.G180Afs*11 4 移码 1 0.016 9
9 c.688G>A p.G230S 5 错义 5 0.081 9
10 c.689+908G>A 不造成氨基酸改变，但可能影响蛋白表达 5 内含子 2 0.032 14
11 c.748C>T p.R250W 6 错义 5 0.081 1
12 c.720delT p.E241NfsX1 6 移码 2 0.032 11
13 c.910A>G p.K304E 7 错义 1 0.016 11
14 c.958C>G p.P320A 7 错义 1 0.016 18
15 c.961T>C p.S321P 7 错义 2 0.032 7
16 c.964G>A p.E322K 7 错义 1 0.016 12
17 c.1149_1160del p.I384_T387del 9 非移码 1 0.016 18
18 c.1193T>C p.L398P 9 错义 2 0.032 10
19 c.1297_1300del p.D433Kfs*20 10 移码 1 0.016 18
20 c.1404delA p.G469Vfs*84 12 移码 2 0.032 12
21 c.1487T>G p.M496R 12 错义 1 0.016 8
22 c.1546T>C p.C516R 13 错义 1 0.016 18
23 c.1571C>T p.A524V 13 错义 1 0.016 18
24 c.1576C>T p.R526X) 13 无义 2 0.032 本文资料
25 c.1655T>G p.V552G 14 错义 1 0.016 12
26 c.1686delG p.D563Tfs*24 14 移码 2 0.032 16
27 c.1765-2_1765-1delAG p.G589 15 错义 2 0.032 7
28 c.1822C>T p.R608W 15 错义 1 0.016 18
29 c.1922C>A p.A641E 16 错义 1 0.016 18
30 c.2011C>T p.R671C 16 错义 11 0.177 12
31 exon14-18dup 不造成氨基酸改变，但可能影响蛋白表达 14~18 重复 1 0.016 18
表 1  联合氧化磷酸化缺陷症1型患者已报道的GFM1基因等位基因突变频率表
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