中国人群33 104例单基因病携带者筛查的多中心研究

doi:10.12122/j.issn.1673-4254.2024.06.01

南方医科大学学报 ›› 2024, Vol. 44 ›› Issue (6): 1015-1023.doi: 10.12122/j.issn.1673-4254.2024.06.01

中国人群33 104例单基因病携带者筛查的多中心研究

侯伟¹, 付晓琳¹, 谢潇潇², 张春燕³, 边佳昕⁴, 毛翛⁵, 文娟⁶, 罗春玉⁷, 金华⁸, 祝茜⁹, 戚庆炜¹⁰, 钱叶青¹¹, 袁静¹², 赵彦艳¹³, 尹爱兰¹⁴, 李树铁¹⁵, 蒋宇林¹⁰, 张蔓丽³(), 肖锐⁴(), 卢彦平¹⁶()

^1.中国人民解放军医学院，北京 100853
^2.中国人民解放军总医院第一医学中心妇产科，北京 100853
^3.中国人民解放军总医院医学创新研究部，北京 100853
^4.浙江博圣生物技术股份有限公司，浙江杭州 310058
^5.湖南省妇幼保健院，湖南长沙 410008
^6.中南大学医学遗传学研究中心，湖南长沙 410083
^7.南京市妇幼保健院遗传医学中心，江苏南京 210011
^8.济南市妇幼保健院孕产医疗保健部，山东济南 250000
^9.四川大学华西第二医院医学遗传科，四川成都 610041
^10.中国医学科学院北京协和医院妇产科，北京 100730
^11.浙江大学医学院附属妇产科医院生殖遗传科，浙江杭州 311215
^12.安徽医科大学第一附属医院产前诊断中心，安徽合肥 230022
^13.中国医科大学附属盛京医院临床遗传科，辽宁沈阳 110004
^14.南方医科大学南方医院妇产科，广东广州 510515
^15.河北北方学院附属第一医院住培办，河北张家口 075061
^16.中国人民解放军总医院第七医学中心妇产医学部，北京 100010

收稿日期:2024-02-22 出版日期:2024-06-20 发布日期:2024-07-05
通讯作者: 张蔓丽,肖锐,卢彦平 E-mail:zhangmanli@301hospital.com.cn;xiaorui@biosan.cn;luyp301@163.com
作者简介:侯伟、付晓琳、谢潇潇共同为第一作者
侯伟、付晓琳、谢潇潇共同为第一作者
侯伟、付晓琳、谢潇潇共同为第一作者
第一联系人：侯伟，在读博士研究生，E-mail: houwei75@126.com
付晓琳，在读硕士研究生，E-mail: fuliner89@163.com
谢潇潇，主治医师，E-mail: x11505764@126.com
基金资助:
国家重点研发计划(2021YFC1005303);军队后勤科研项目计划生育专项课题(23JSZ17)

Carrier screening for 223 monogenic diseases in Chinese population: a multi-center study in 33 104 individuals

Wei HOU¹, Xiaolin FU¹, Xiaoxiao XIE², Chunyan ZHANG³, Jiaxin BIAN⁴, Xiao MAO⁵, Juan WEN⁶, Chunyu LUO⁷, Hua JIN⁸, Qian ZHU⁹, Qingwei QI¹⁰, Yeqing QIAN¹¹, Jing YUAN¹², Yanyan ZHAO¹³, Ailan YIN¹⁴, Shutie LI¹⁵, Yulin JIANG¹⁰, Manli ZHANG³(), Rui XIAO⁴(), Yanping LU¹⁶()

^1.Medical School of Chinese People's Liberation Army, Beijing 100853, China
^2.Department of Gynecology and Obstetrics, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
^3.Medical Innovation Research Division, Chinese PLA General Hospital, Beijing 100853, China
^4.Zhejiang Biosan Biochemical Technologies Co. Ltd, Hangzhou 310058, China
^5.Hunan Provincial Maternal and Child Health Care Hospital, Changsha 410008, China
^6.Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410083, China
^7.Center for Medical Genetics, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210011, China
^8.Department of Obstetrics and Gynecology, Jinan Maternity and Child Care Hospital, Jinan 250000, China
^9.Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu 610041, China
^10.Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China
^11.Department of Reproductive Genetics, Women's Hospital, School of Medicine Zhejiang University, Hangzhou 311215, China
^12.Center for Prenatal Diagnosis, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
^13.Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang 110004, China
^14.Department of Gynecology and Obstetrics, Nanfang Hospital of Southern Medical University, Guangzhou 510515, China
^15.Office of Standardized Training of Residents, First Affiliated Hospital of Hebei North University, Zhangjiakou 075061, China
^16.Department of Gynecology and Obstetrics, Seventh Medical Center of PLA General Hospital, Beijing 100010, China

Received:2024-02-22 Online:2024-06-20 Published:2024-07-05
Contact: Manli ZHANG, Rui XIAO, Yanping LU E-mail:zhangmanli@301hospital.com.cn;xiaorui@biosan.cn;luyp301@163.com

摘要/Abstract

摘要：

目的通过大规模多中心的多种遗传病携带者筛查，调查中国人群单基因病的流行病学特征以及突变谱，为制定适合中国人群的遗传病预防策略提供依据。方法本研究在中国的12个临床中心共招募33 104例受检者（16 610例女性），基于高通量测序和多种PCR对223个基因的携带者状态进行检测。结果 197个常染色体基因的合并携带者频率为55.58%，26个X连锁基因的合并携带者频率为1.84%。在16 669例家系中，共检出874对（5.24%）高危夫妇。其中常染色体基因高危夫妇584对（3.50%），X连锁基因高危夫妇306对（1.84%），16对夫妇同时为常染色体基因和X连锁基因高危夫妇。最常检出的常染色体高危基因包括GJB2（常染色体隐性耳聋1A，393对），HBA1/HBA2（α-地中海贫血，36对）和PAH（苯丙酮尿症，14对），SMN1（脊髓性肌萎缩症，14对）。最常检出的X连锁高危基因包括G6PD（G6PD缺乏症，236对），DMD（进行性假肥大性肌营养不良，23对）和FMR1（脆性X综合征，17对）。除外G6PD后的高危夫妇率为3.91%（651/16 669），进一步除外GJB2 c.109G>A位点后，高危夫妇率为1.72%（287/16 669）。理论上严重的单基因病出生缺陷的发病率约为4.35‰（72.5/16 669）。对导致高危夫妇最多的22个基因进行筛查可检出95%以上的高危夫妇，对导致高危夫妇最多的54个基因进行筛查可检出99%以上的高危夫妇。结论本研究揭示了我国人群中223种单基因病的携带者频率，为中国人群的携带者筛查策略制定和panel设计提供依据。在携带者筛查实践中，针对某些特殊基因或变异位点的遗传咨询可能会面临困难。这些特殊基因或变异需要在检测前告知受检夫妇，并在可能的情况下提供不筛查这些基因或变异的选择。

关键词: 携带者筛查, 单基因病, 遗传咨询

Abstract:

Objective To investigate the epidemiological characteristics and mutation spectrum of monogenic diseases in Chinese population through a large-scale, multicenter carrier screening. Methods This study was conducted among a total of 33 104 participants (16 610 females) from 12 clinical centers across China. Carrier status for 223 genes was analyzed using high-throughput sequencing and different PCR methods. Results The overall combined carrier frequency was 55.58% for 197 autosomal genes and 1.84% for 26 X-linked genes in these participants. Among the 16 669 families, 874 at-risk couples (5.24%) were identified. Specifically, 584 couples (3.50%) were at risk for autosomal genes, 306 (1.84%) for X-linked genes, and 16 for both autosomal and X-linked genes. The most frequently detected autosomal at-risk genes included GJB2 (autosomal recessive deafness type 1A, 393 couples), HBA1/HBA2 (α-thalassemia, 36 couples), PAH (phenylketonuria, 14 couples), and SMN1 (spinal muscular atrophy, 14 couples). The most frequently detected X-linked at-risk genes were G6PD (G6PD deficiency, 236 couples), DMD (Duchenne muscular dystrophy, 23 couples), and FMR1 (fragile X syndrome, 17 couples). After excluding GJB2 c.109G>A, the detection rate of at-risk couples was 3.91% (651/16 669), which was lowered to 1.72% (287/16 669) after further excluding G6PD. The theoretical incidence rate of severe monogenic birth defects was approximately 4.35‰ (72.5/16 669). Screening for a battery of the top 22 most frequent genes in the at-risk couples could detect over 95% of at-risk couples, while screening for the top 54 genes further increased the detection rate to over 99%. Conclusion This study reveals the carrier frequencies of 223 monogenic genetic disorders in the Chinese population and provides evidence for carrier screening strategy development and panel design tailored to the Chinese population. In carrier testing, genetic counseling for specific genes or gene variants can be challenging, and the couples need to be informed of these difficulties before testing and provided with options for not screening these genes or gene variants.

Key words: genetic carrier screening, monogenic disorders, genetic counseling

侯伟, 付晓琳, 谢潇潇, 张春燕, 边佳昕, 毛翛, 文娟, 罗春玉, 金华, 祝茜, 戚庆炜, 钱叶青, 袁静, 赵彦艳, 尹爱兰, 李树铁, 蒋宇林, 张蔓丽, 肖锐, 卢彦平. 中国人群33 104例单基因病携带者筛查的多中心研究[J]. 南方医科大学学报, 2024, 44(6): 1015-1023.

Wei HOU, Xiaolin FU, Xiaoxiao XIE, Chunyan ZHANG, Jiaxin BIAN, Xiao MAO, Juan WEN, Chunyu LUO, Hua JIN, Qian ZHU, Qingwei QI, Yeqing QIAN, Jing YUAN, Yanyan ZHAO, Ailan YIN, Shutie LI, Yulin JIANG, Manli ZHANG, Rui XIAO, Yanping LU. Carrier screening for 223 monogenic diseases in Chinese population: a multi-center study in 33 104 individuals[J]. Journal of Southern Medical University, 2024, 44(6): 1015-1023.

图/表 5

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Gene	Carrier frequency*	Inheritance	Gene	Carrier frequency*	Inheritance
GJB2	13.44%	AR/AD/DD	ACADS	0.99%	AR
HBA1/HBA2	3.12%	AD	TYR	0.98%	AR/AD
PAH	2.87%	AR	HBB	0.96%	AR/AD
ATP7B	2.77%	AR	PKHD1	0.94%	AR
SLC26A4	2.65%	AR	MMUT	0.90%	AR
GALC	2.52%	AR	CYP27A1	0.86%	AR
CYP21A2	2.09%	AR	ABCG5	0.71%	AR
POLG	2.06%	AR/AD	CAPN3	0.70%	AR/AD
SMN1	1.87%	AR	ETFDH	0.69%	AR
USH2A	1.85%	AR	CFTR	0.66%	AR/AD
SLC22A5	1.77%	AR	PTS	0.66%	AR
MMACHC	1.76%	AR	MCPH1	0.64%	AR
SLC25A13	1.75%	AR	ALPL	0.64%	AR/AD
G6PD	1.45%	XL	G6PC1	0.63%	AR
GAA	1.15%	AR	CEP290	0.56%	AR
ACADSB	1.07%	AR	AGXT	0.53%	AR
UGT1A1	1.03%	AR/AD
* Only P/LP variants are considered.

Gene	Carrier frequency*	Inheritance	Gene	Carrier frequency*	Inheritance
GJB2	13.44%	AR/AD/DD	ACADS	0.99%	AR
HBA1/HBA2	3.12%	AD	TYR	0.98%	AR/AD
PAH	2.87%	AR	HBB	0.96%	AR/AD
ATP7B	2.77%	AR	PKHD1	0.94%	AR
SLC26A4	2.65%	AR	MMUT	0.90%	AR
GALC	2.52%	AR	CYP27A1	0.86%	AR
CYP21A2	2.09%	AR	ABCG5	0.71%	AR
POLG	2.06%	AR/AD	CAPN3	0.70%	AR/AD
SMN1	1.87%	AR	ETFDH	0.69%	AR
USH2A	1.85%	AR	CFTR	0.66%	AR/AD
SLC22A5	1.77%	AR	PTS	0.66%	AR
MMACHC	1.76%	AR	MCPH1	0.64%	AR
SLC25A13	1.75%	AR	ALPL	0.64%	AR/AD
G6PD	1.45%	XL	G6PC1	0.63%	AR
GAA	1.15%	AR	CEP290	0.56%	AR
ACADSB	1.07%	AR	AGXT	0.53%	AR
UGT1A1	1.03%	AR/AD
* Only P/LP variants are considered.

Gene	At-Risk couples*	Inheritance	Gene	At-Risk couples*	Inheritance
GJB2	393	AR/AD/DD	ACADS	2	AR
G6PD	236	XL	HBB	2	AR/AD
HBA1/HBA2	36	AD	CAPN3	2	AR/AD
DMD	23	XL/XLR	CFTR	2	AR/AD
FMR1	17	XL/XLD	ALPL	2	AR/AD
PAH	14	AR	CEP290	2	AR
SMN1	14	AR	ACADM	2	AR
SLC26A4	12	AR	NPHS1	2	AR
CYP21A2	11	AR	FANCA	2	AR
MMACHC	10	AR	ABCD1	1	XLR
GLA	9	XL	CYP27A1	1	AR
POLG	9	AR/AD	OTC	1	XL
ATP7B	8	AR	F9	1	XLR
F8	7	XLR	RS1	1	XLR
UGT1A1	7	AR/AD	COL4A5	1	XLD
GALC	6	AR	OCRL	1	XLR
SLC22A5	6	AR	PTS	1	AR
SLC25A13	6	AR	PRF1	1	AR
MMUT	6	AR	SLC26A2	1	AR
USH2A	5	AR	CC2D2A	1	AR
AFF2	4	XLR	GCDH	1	AR
PKHD1	4	AR	TH	1	AR
GAA	3	AR	GBA1	1	AR
ABCG5	3	AR	EVC2	1	AR/AD
ETFDH	3	AR	ALDOB	1	AR
PMM2	3	AR	NPC1	1	AR
MTM1	2	XLR	AHI1	1	AR
ACADSB	2	AR	GLB1	1	AR
CYBB	2	XLR
* Only P/LP variants are considered.

Gene	At-Risk couples*	Inheritance	Gene	At-Risk couples*	Inheritance
GJB2	393	AR/AD/DD	ACADS	2	AR
G6PD	236	XL	HBB	2	AR/AD
HBA1/HBA2	36	AD	CAPN3	2	AR/AD
DMD	23	XL/XLR	CFTR	2	AR/AD
FMR1	17	XL/XLD	ALPL	2	AR/AD
PAH	14	AR	CEP290	2	AR
SMN1	14	AR	ACADM	2	AR
SLC26A4	12	AR	NPHS1	2	AR
CYP21A2	11	AR	FANCA	2	AR
MMACHC	10	AR	ABCD1	1	XLR
GLA	9	XL	CYP27A1	1	AR
POLG	9	AR/AD	OTC	1	XL
ATP7B	8	AR	F9	1	XLR
F8	7	XLR	RS1	1	XLR
UGT1A1	7	AR/AD	COL4A5	1	XLD
GALC	6	AR	OCRL	1	XLR
SLC22A5	6	AR	PTS	1	AR
SLC25A13	6	AR	PRF1	1	AR
MMUT	6	AR	SLC26A2	1	AR
USH2A	5	AR	CC2D2A	1	AR
AFF2	4	XLR	GCDH	1	AR
PKHD1	4	AR	TH	1	AR
GAA	3	AR	GBA1	1	AR
ABCG5	3	AR	EVC2	1	AR/AD
ETFDH	3	AR	ALDOB	1	AR
PMM2	3	AR	NPC1	1	AR
MTM1	2	XLR	AHI1	1	AR
ACADSB	2	AR	GLB1	1	AR
CYBB	2	XLR
* Only P/LP variants are considered.

Gene	Location	c.change	p.change	Counts	Proportion in mutation spectrum
GJB2	chr13:20763612	c.109G>A	p.V37I	3469	77.99%
GALC	chr14:88406259	c.1901T>C	p.L634S	701	83.85%
POLG	chr15:89864088	c.2890C>T	p.R964C	631	92.52%
GJB2	chr13:20763485	c.235del	p.L79Cfs	628	14.12%
SMN1	SMN1-E7-DEL	exon7del	-	620	100.00%
HBA1/HBA2	HBA1_HBA2-3.7-DEL	-	-	547	52.90%
SLC26A4	chr7:107323898	c.919-2A>G	-	385	43.80%
SLC22A5	chr5:131728257	c.1400C>G	p.S467C	324	55.20%
HBA1/HBA2	HBA1_HBA2-SEA-DEL	-	-	290	28.05%
SLC25A13	chr7:95818683	c.852_855del	p.M285Pfs	274	47.32%
UGT1A1	chr2:234681059	c.1456T>G	p.Y486D	271	79.24%
USH2A	chr1:216419934	c.2802T>G	p.C934W	260	42.48%
ATP7B	chr13:52532469	c.2333G>T	p.R778L	209	22.82%
CYP21A2	chr6:32007887	c.844G>T	p.V282L	202	29.23%
MCPH1	chr8:6338233	c.1974-2A>G	-	165	77.46%
PKHD1	chr6:51910887	c.2507T>C	p.V836A	159	50.96%
MMACHC	chr1:45974647	c.609G>A	p.W203X	157	26.98%
GAA	chr17:78081415	c.[752C>T;761C>T]	p.[S251L;S254L]	154	40.42%
GJB2	chr13:20763420	c.299_300del	p.H100Rfs	148	3.33%
CYP21A2	chr6:32006858	c.293-13C>G	-	148	21.42%
ATP7B	chr13:52516618	c.3316G>A	p.V1106I	142	15.50%
CAPN3	chr15:42702630	c.2120A>G	p.D707G	140	60.09%
ACADS	chr12:121176944	c.1031A>G	p.E344G	113	34.66%
GNE	chr9:36246117	c.527A>T	p.D176V	112	79.43%
ACADSB	chr10:124800869	c.655G>A	p.V219M	105	29.66%
SLC25A13	SLC25A13-IVS16ins3kb	IVS16ins3kb	p.A584Vfs	101	17.44%
CYP21A2	chr6:32007203	c.518T>A	p.I173N	100	14.47%
G6PC1	chr17:41059645	c.446G>A	p.R149Q	96	46.38%
SLC26A4	chr7:107350577	c.2168A>G	p.H723R	95	10.81%
ABCG5	chr2:44050063	c.1336C>T	p.R446X	93	39.74%
PAH	chr12:103246707	c.728G>A	p.R243Q	89	9.34%
HBB	chr11:5247153	c.316-197C>T	-	87	27.53%
PRF1	chr10:72360156	c.503G>A	p.S168N	87	54.72%
ACADSB	chr10:124812613	c.1165A>G	p.M389V	83	23.45%
PAH	chr12:103249104	c.516G>T	p.Q172H	83	8.71%
ETFDH	chr4:159616734	c.770A>G	p.Y257C	82	35.81%
AGXT	chr2:241808314	c.32C>G	p.P11R	82	46.59%
HBA1/HBA2	HBA2-4.2-DEL	-	-	81	7.83%
ABCG5	chr2:44051210	c.1166G>A	p.R389H	78	33.33%
GALT	chr9:34648988	c.821-7A>G	-	78	69.03%

中国人群33 104例单基因病携带者筛查的多中心研究

Carrier screening for 223 monogenic diseases in Chinese population: a multi-center study in 33 104 individuals

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