石家庄地区3-甲基巴豆酰辅酶A羧化酶缺乏症患病率及MCCC1、MCCC2基因变异分析

doi:10.12280/gjszjk.20220495

摘要/Abstract

摘要： 目的： 初步明确3-甲基巴豆酰辅酶A羧化酶缺乏症（3-methylcrotonyl-CoA carboxylase deficiency，MCCD）在石家庄地区新生儿中的患病率及基因变异特点。方法： 采用串联质谱技术对石家庄地区2014年1月—2021年12月出生的185 683例新生儿进行MCCD筛查，对筛查阳性患儿进行3-甲基巴豆酰辅酶A羧化酶1（3-methylcrotonyl-CoA carboxylase 1，MCCC1）基因和MCCC2基因变异分析，随访患儿的生长发育情况。结果： 确诊2例患儿，患病率为1.08/10万；其中1例为MCCD2型，基因分析检测到MCCC2基因复合杂合变异，基因型为c.592C>T和c.1144_1147delAAAAinsTTTT，其中c.592C>T为致病性变异，c.1144_1147delAAAAinsTTTT为未报道基因变异，致病性评级为疑似致病；串联质谱筛查结果提示患儿血3-羟基异戊酰肉碱（3-hydroxyisovalerylcarnitine，C5OH）水平升高，初筛C5OH水平为12.26 μmol/L（正常值0.07~0.61 μmol/L），随访至1岁3个月患儿生长发育正常，为无症状型。另1例为母源性MCCD 1型，患儿初筛血C5OH水平升高，为6.28 μmol/L， 6个月后降至0.75 μmol/L，基本正常；患儿基因检测结果为MCCC1杂合变异，基因变异为c.1679_1680insA，为尚未报道基因变异，致病性评级为疑似致病；患儿随访至4岁3个月，发育正常。结论： 初步明确了MCCD在石家庄地区新生儿中的患病率为1.08/10万；发现了3种基因变异位点，其中2种为未报道基因变异，丰富了MCCC1、MCCC2基因变异谱，为遗传咨询提供了依据。

关键词: 婴儿，新生，疾病, 3-甲基巴豆酰辅酶A羧化酶缺乏症, 患病率, 基因, 遗传变异

Abstract: Objective: To determine the prevalence of 3-methylcrotonyl-CoA carboxylase deficiency (MCCD) in neonates in Shijiazhuang City, and to test the mutations of the related genes.Methods: 185 683 neonates born in Shijiazhuang City were screened for MCCD by tandem mass spectrometry from January 2014 to December 2021, and the gene mutations of MCCC1 and MCCC2 were analyzed in those screened positive neonates. The growth and development of positive neonates were followed up. Results: Two children were diagnosed, with a prevalence of 1.08/100 000. Among them, one case was MCCD2 type with a complex heterozygous variation, which were c.592C>T and c.1144_1147delAAAAinsTTTT. The mutation of c.592C>T was a pathogenic variation while the c.1144_1147delAAAAinsTTTT was an unreported mutation, so its pathogenicity was classified as a suspected pathogenicity. The results of tandem mass spectrometry screening showed that the level of serum C5OH in the child with gene mutaion was increased. The initial screening level of C5OH was 12.26 μmol/L (normal value range is 0.07-0.61 μmol/L). The growth and development was normal during 1 year and 3 months of following up. The another child with the maternal MCCD 1 type was also tested. The primary screening level of C5OH increased to 6.28 μmol/L, and reduced to 0.75 μmol/L within the normal range after 6 months. The MCCC1 heterozygous variation was c.1679_1680insA, which was an unreported gene mutation, and the pathogenicity is classified as suspected pathogenicity. The development of this child was normal during 4 years and 3 months of following up. Conclusions: The prevalence of MCCD in neonates in Shijiazhuang area is 1.08/100 000. Three gene variation sites were found, two of which were unreported gene variations. These results enrich the variation spectrum of MCCC1 and MCCC2 genes, and provid a basis for genetic counseling.

Key words: Infant, newborn, diseases, 3-methylcrotonoyl CoA carboxylase deficiency, Prevalence, Genes, Genetic variation

贾立云, 王熙, 马翠霞, 杨会欣, 弓苗, 封纪珍. 石家庄地区3-甲基巴豆酰辅酶A羧化酶缺乏症患病率及MCCC1、MCCC2基因变异分析[J]. 国际生殖健康/计划生育杂志, 2023, 42(2): 111-114.

JIA Li-yun, WANG Xi, MA Cui-xia, YANG Hui-xin, GONG Miao, FENG Ji-zhen. Analysis of Prevalence of 3-Methylcrotonyl-CoA Carboxylase Deficiency and Mutations of MCCC1 and MCCC2 Genes in Shijiazhuang Area[J]. Journal of International Reproductive Health/Family Planning, 2023, 42(2): 111-114.

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病例编号	初筛	复查	随访	参考值范围
例1	C5OH:12.26	C5OH:15.43	-	C5OH:0.07~0.61
	C0:9.89	C0:3.08		C0:7~51.4
例2	C5OH:6.28	-	C5OH:0.75	C5OH:0.07~0.61
	C0:9.44		C0:36.27	C0:7~51.4

病例编号	初筛	复查	随访	参考值范围
例1	C5OH:12.26	C5OH:15.43	-	C5OH:0.07~0.61
	C0:9.89	C0:3.08		C0:7~51.4
例2	C5OH:6.28	-	C5OH:0.75	C5OH:0.07~0.61
	C0:9.44		C0:36.27	C0:7~51.4

病例编号	基因	基因亚区	核苷酸改变	氨基酸改变	致病性评级	纯合/ 杂合	来源	相关疾病/ 遗传方式
例1	MCCC2	EX6	c.592C>T	p.Gln198^#	致病	杂合	母亲	MCCD 2型/AR
	MCCC2	EX12	c.1144_1147delAAAAinsTTTT^△	p.Lys382_Met563del insPhe	疑似致病	杂合	父亲	MCCD 2型/AR
例2	MCCC1	EX14	c.1679_1680insA	p.Asn560Lysfs*10	疑似致病	杂合	母亲	MCCD 1型/AR

病例编号	基因	基因亚区	核苷酸改变	氨基酸改变	致病性评级	纯合/ 杂合	来源	相关疾病/ 遗传方式
例1	MCCC2	EX6	c.592C>T	p.Gln198^#	致病	杂合	母亲	MCCD 2型/AR
	MCCC2	EX12	c.1144_1147delAAAAinsTTTT^△	p.Lys382_Met563del insPhe	疑似致病	杂合	父亲	MCCD 2型/AR
例2	MCCC1	EX14	c.1679_1680insA	p.Asn560Lysfs*10	疑似致病	杂合	母亲	MCCD 1型/AR