人全外显子组测序IDT捕获探针的性能验证

doi:10.3877/cma.j.issn.2095-5820.2020.02.005

中华临床实验室管理电子杂志 ›› 2020, Vol. 08 ›› Issue (02) : 87 -93. doi: 10.3877/cma.j.issn.2095-5820.2020.02.005

所属专题：文献；

实验研究

人全外显子组测序IDT捕获探针的性能验证

孙明明¹, 刘菲菲¹, 欧小华², 胡昌明², 毛琳琳¹, 赵薇薇¹^,^†(

)

^1. 510005　广州，广州金域医学检验中心有限公司，临床基因组检测中心；510005　广州，广州金域医学检验集团股份有限公司
^2. 510005　广州，广州金域医学检验中心有限公司，临床基因组检测中心

收稿日期:2019-09-22 出版日期:2020-05-28
通信作者: 赵薇薇
基金资助:
广州市产业领军人才集聚工程(CXLJTD-201603); 广州市科技计划项目(201604046001)

Performance verification of IDT capture probes for human Whole-exome sequencing

Mingming Sun¹, Feifei Liu¹, Xiaohua Ou², Changming Hu², Linlin Mao¹, Weiwei Zhao¹^,^†()

^1. Clinical Genome Center, KingMed Center for Clinical Laboratory Co., Ltd., Guangzhou 510005, China; Guangzhou KingMed Diagnostics Group Co., Ltd., Guangzhou 510005, China
^2. Clinical Genome Center, KingMed Center for Clinical Laboratory Co., Ltd., Guangzhou 510005, China

Received:2019-09-22 Published:2020-05-28
Corresponding author: Weiwei Zhao
About author:
Corresponding author: Zhao Weiwei, Email: lab-zhaoweiwei@kingmed.com.cn

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引用本文：

孙明明, 刘菲菲, 欧小华, 胡昌明, 毛琳琳, 赵薇薇. 人全外显子组测序IDT捕获探针的性能验证[J/OL]. 中华临床实验室管理电子杂志, 2020, 08(02): 87-93.

Mingming Sun, Feifei Liu, Xiaohua Ou, Changming Hu, Linlin Mao, Weiwei Zhao. Performance verification of IDT capture probes for human Whole-exome sequencing[J/OL]. Chinese Journal of Clinical Laboratory Management(Electronic Edition), 2020, 08(02): 87-93.

目的

探讨已建立的二代测序技术进行人全外显子组测序项目对变异的检出性能。

方法

对4例实验室能力比对验证样本和4例已知结果样本进行全外显子组检测，分析点变异和插入缺失变异，从检测准确度、检测灵敏度、检测特异性、精密度和可报告范围等方面进行性能评估。数据质量控制以目标区域覆盖率、捕获特异性和平均深度为基础。

结果

数据输出量大于8G，实现了目标序列区域99.7%以上的覆盖率，捕获特异性86%以上，平均测序深度100×以上，Q30大于90%，对SNV的检出率达100%，50 bp以下Indel检出率达100%。

结论

本标准操作在验证范围内对变异的检出能力达到应用的要求。

关键词: 全外显子组, 验证, 灵敏度, 特异性, 准确度

Objective

To investigate the detection performance of Whole-exome sequencing (WES) for calling variants by the established second-generation sequencing technology.

Methods

Four CAP proficiency testing samples and 4 known results samples were detected by WES. Point mutations and insertion deletion mutations were analyzed. Detection performance was evaluated in terms of accuracy, sensitivity, specificity, precision and reportable range of calling variants. Data quality control was performed based on coverage of target region, capture specificity and mean depth.

Results

Output data should not be less than 8G. In this case, coverage of target region is over 99.7%. Capture specificity is over 86%. Mean depth is over 100×. Q30 is over 90%, The detection of single nucleotide variations and small insertion and deletion under 50bp is up to 100%.

Conclusion

The standard operating procedure within the scope of validation can meet the application requirement of mutation detection.

Key words: Whole-exome sequencing, Verification, Sensitivity, Specificity, Accuracy

图1 生物信息学分析

表1 原始数据分析质控参数及参考值

Raw Data QC	参考范围	本研究样本数据平均值
Total reads/sample (M)	≥50	67.18
Total base/sample (G)	≥8	9.94
Mapped rate (%)	≥99	99.86
Mean depth of target region (×)	≥100	140.45
Duplication Rate (%)	<5	2.91
Capture specificity (%)	≥80	83.99
Coverage of target region (%)	≥99	99.83
Percent of target region ≥20×(%)	≥95	99.63

表1 原始数据分析质控参数及参考值

Raw Data QC	参考范围	本研究样本数据平均值
Total reads/sample (M)	≥50	67.18
Total base/sample (G)	≥8	9.94
Mapped rate (%)	≥99	99.86
Mean depth of target region (×)	≥100	140.45
Duplication Rate (%)	<5	2.91
Capture specificity (%)	≥80	83.99
Coverage of target region (%)	≥99	99.83
Percent of target region ≥20×(%)	≥95	99.63

表2 5例样本8个SNV的NGS检测结果

样本号	样本已知的SNV阳性位点	NGS检测结果
样本号	样本已知的SNV阳性位点	覆盖度(×)	频率(%)
MGL4-14	SMPD1:NM_000543:c.1493G>T(p.R498L)	85	40
MGL4-14	GBA:NM_000157:c.1226A>G(p.N409S)	86	54.1
MGL4-18	MCOLN1:NM_020533:c.406-2A>G	22	100
NP15D315	C7:NM_000587:c.281-1G>T	41	24.4
NP15D2229	CDAN1:NM_138477:c.3331C>T(p.R1111*)	116	67
NP15D2229	FANCA:NM_000135:c.1108G>T(p.E370*)	113	50.4
NP15D2572	IFIH1:NM_022168:c.2647G>C(p.E883Q)	29	48.3
NP15D2572	COL6A3:NM_004369:c.6857A>C(p.N2286T)	45	36.4

表2 5例样本8个SNV的NGS检测结果

样本号	样本已知的SNV阳性位点	NGS检测结果
样本号	样本已知的SNV阳性位点	覆盖度(×)	频率(%)
MGL4-14	SMPD1:NM_000543:c.1493G>T(p.R498L)	85	40
MGL4-14	GBA:NM_000157:c.1226A>G(p.N409S)	86	54.1
MGL4-18	MCOLN1:NM_020533:c.406-2A>G	22	100
NP15D315	C7:NM_000587:c.281-1G>T	41	24.4
NP15D2229	CDAN1:NM_138477:c.3331C>T(p.R1111*)	116	67
NP15D2229	FANCA:NM_000135:c.1108G>T(p.E370*)	113	50.4
NP15D2572	IFIH1:NM_022168:c.2647G>C(p.E883Q)	29	48.3
NP15D2572	COL6A3:NM_004369:c.6857A>C(p.N2286T)	45	36.4

表3 6例样本9个Indel的NGS检测结果

样本号	PT/已知结果	NGS检测结果
样本号	PT/已知结果	覆盖度(×)	频率(%)
MGL4-10	HEXA:NM_000520:c.1274-1277dupTATC	61	100
MGL4-13	BLM:NM_000057:c.2207-2212delinsTAGATTC	9	100
MGL4-14	SMPD1:NM_000543:c.1829-1831delGCC	60	36.8
R5806	TSC2:NM_000548:c.4135_4143dupTCGCAGCCC	87	43.4
	GAA:NM_000152:c.2024_2026delACA	52	29.4
	GAA:NM_000152:c.2312delC	133	37
NP15D315	CD59:NM_203329:c.29delT	47	44.4
NP15D315	CD59:NM_203329:c.283_354del72	85	未检测到
NP15D2572	SLC25A13:NM_014251:c.852_855delTATG	27	29.7

表3 6例样本9个Indel的NGS检测结果

样本号	PT/已知结果	NGS检测结果
样本号	PT/已知结果	覆盖度(×)	频率(%)
MGL4-10	HEXA:NM_000520:c.1274-1277dupTATC	61	100
MGL4-13	BLM:NM_000057:c.2207-2212delinsTAGATTC	9	100
MGL4-14	SMPD1:NM_000543:c.1829-1831delGCC	60	36.8
R5806	TSC2:NM_000548:c.4135_4143dupTCGCAGCCC	87	43.4
	GAA:NM_000152:c.2024_2026delACA	52	29.4
	GAA:NM_000152:c.2312delC	133	37
NP15D315	CD59:NM_203329:c.29delT	47	44.4
NP15D315	CD59:NM_203329:c.283_354del72	85	未检测到
NP15D2572	SLC25A13:NM_014251:c.852_855delTATG	27	29.7

表4 4例CAP PT标本阴性位点的NGS检测结果

样本号	PT结果	NGS检测结果	覆盖度(×)	频率(%)
MGL4-10	ASPA: No variant	NM_000049:c.693C>T(p.Y231Y)	56	50
	IKBKAP: No variant	NM_003640:c.3473C>T(p.P1158L)	36	100
		NM_003640:c.3214T>A(p.C1072S)	83	100
		NM_003640:c.441G>A(p.Q147Q)	55	100
MGL4-13	GBA: No variant	No variant detected	-	-
	SMPD1: No variant : No variant	NM_000543:c.138_143delGCTGGC	119	100
	SMPD1: No variant : No variant	NM_000543:c.636T>C(p.D212D)	36	55.6
MGL4-14	BLM: No variant	No variant detected	-	-
MGL4-18	FANCC: No variant : No variant : No variant	N-UTR3	64	100
		N-UTR3	81	61.2
		N-UTR3	87	58.6
	G6PC: No variant	No variant detected	-	-

表4 4例CAP PT标本阴性位点的NGS检测结果

样本号	PT结果	NGS检测结果	覆盖度(×)	频率(%)
MGL4-10	ASPA: No variant	NM_000049:c.693C>T(p.Y231Y)	56	50
	IKBKAP: No variant	NM_003640:c.3473C>T(p.P1158L)	36	100
		NM_003640:c.3214T>A(p.C1072S)	83	100
		NM_003640:c.441G>A(p.Q147Q)	55	100
MGL4-13	GBA: No variant	No variant detected	-	-
	SMPD1: No variant : No variant	NM_000543:c.138_143delGCTGGC	119	100
	SMPD1: No variant : No variant	NM_000543:c.636T>C(p.D212D)	36	55.6
MGL4-14	BLM: No variant	No variant detected	-	-
MGL4-18	FANCC: No variant : No variant : No variant	N-UTR3	64	100
		N-UTR3	81	61.2
		N-UTR3	87	58.6
	G6PC: No variant	No variant detected	-	-

表5 2例CAP PT标本NGS检测结果说明

样本号	基因	NGS检测结果	千人基因组数据库频率(%)	金域遗传病数据库频率(%)	Clinvar(20170130)
MGL4-10	ASPA	NM_000049:c.693C>T(p.Y231Y)	20	50	likely benign
	IKBKAP	NM_003640:c.3473C>T(p.P1158L)	25	51	likely benign
		NM_003640:c.3214T>A(p.C1072S)	25	51	likely benign
		NM_003640:c.441G>A(p.Q147Q)	8	17.7	likely benign
MGL4-13	SMPD1	NM_000543:c.138_143delGCTGGC	0	29	benign
MGL4-13	SMPD1	NM_000543:c.636T>C(p.D212D)	15	0.9	likely benign

表5 2例CAP PT标本NGS检测结果说明

样本号	基因	NGS检测结果	千人基因组数据库频率(%)	金域遗传病数据库频率(%)	Clinvar(20170130)
MGL4-10	ASPA	NM_000049:c.693C>T(p.Y231Y)	20	50	likely benign
	IKBKAP	NM_003640:c.3473C>T(p.P1158L)	25	51	likely benign
		NM_003640:c.3214T>A(p.C1072S)	25	51	likely benign
		NM_003640:c.441G>A(p.Q147Q)	8	17.7	likely benign
MGL4-13	SMPD1	NM_000543:c.138_143delGCTGGC	0	29	benign
MGL4-13	SMPD1	NM_000543:c.636T>C(p.D212D)	15	0.9	likely benign

表6 4例样本7个SNV两次检测的结果比较

实验号	PT/已知结果	第一次检测		第二次检测
实验号	PT/已知结果	覆盖度(×)	频率(%)	覆盖度(×)	频率(%)
MGL4-14	SMPD1:NM_000543:c.1493G>T(p.R498L)	85	40	92	32.2
MGL4-14	GBA:NM_000157:c.1226A>G(p.N409S)	86	54.1	71	59.2
MGL4-18	MCOLN1:NM_020533:c.406-2A>G	22	100	17	94.1
NP15D2229	CDAN1:NM_138477:c.3331C>T(p.R1111*)	116	67	126	58.7
NP15D2229	FANCA:NM_000135:c.1108G>T(p.E370*)	113	50.4	98	43.9
NP15D2572	IFIH1:NM_022168:c.2647G>C(p.E883Q)	29	48.3	35	68.6
NP15D2572	COL6A3:NM_004369:c.6857A>C(p.N2286T)	45	36.4	71	47.9

表6 4例样本7个SNV两次检测的结果比较

实验号	PT/已知结果	第一次检测		第二次检测
实验号	PT/已知结果	覆盖度(×)	频率(%)	覆盖度(×)	频率(%)
MGL4-14	SMPD1:NM_000543:c.1493G>T(p.R498L)	85	40	92	32.2
MGL4-14	GBA:NM_000157:c.1226A>G(p.N409S)	86	54.1	71	59.2
MGL4-18	MCOLN1:NM_020533:c.406-2A>G	22	100	17	94.1
NP15D2229	CDAN1:NM_138477:c.3331C>T(p.R1111*)	116	67	126	58.7
NP15D2229	FANCA:NM_000135:c.1108G>T(p.E370*)	113	50.4	98	43.9
NP15D2572	IFIH1:NM_022168:c.2647G>C(p.E883Q)	29	48.3	35	68.6
NP15D2572	COL6A3:NM_004369:c.6857A>C(p.N2286T)	45	36.4	71	47.9

表7 3例样本5个Indel两次检测的结果比较

实验号	PT/已知结果	第一次检测		第二次检测
实验号	PT/已知结果	覆盖度(×)	频率(%)	覆盖度(×)	频率(%)
MGL4-10	HEXA:NM_000520:c.1274-1277dupTATC	61	100	39	100
R5806	TSC2:NM_000548:c.4135_4143dupTCGCAGCCC	87	43.4	73	42.5
	GAA:NM_000152:c.2024_2026delACA	52	29.4	64	56.2
	GAA:NM_000152:c.2312delC	133	37	116	43.4
NP15D2572	SLC25A13:NM_014251:c.852_855delTATG	27	29.7	48	34.8

表7 3例样本5个Indel两次检测的结果比较

实验号	PT/已知结果	第一次检测		第二次检测
实验号	PT/已知结果	覆盖度(×)	频率(%)	覆盖度(×)	频率(%)
MGL4-10	HEXA:NM_000520:c.1274-1277dupTATC	61	100	39	100
R5806	TSC2:NM_000548:c.4135_4143dupTCGCAGCCC	87	43.4	73	42.5
	GAA:NM_000152:c.2024_2026delACA	52	29.4	64	56.2
	GAA:NM_000152:c.2312delC	133	37	116	43.4
NP15D2572	SLC25A13:NM_014251:c.852_855delTATG	27	29.7	48	34.8

表8 4例样本7个SNV的两次检测结果比较

实验号	突变内容	第一次检测		第二次检测
实验号	突变内容	覆盖度(×)	频率(%)	覆盖度(×)	频率(%)
MGL4-14	SMPD1:NM_000543:c.1493G>T(p.R498L)	92	32.2	130	41.9
MGL4-14	GBA:NM_000157:c.1226A>G(p.N409S)	71	59.2	113	41.1
MGL4-18	MCOLN1:NM_020533:c.406-2A>G	17	94.1	75	100
NP15D2229	CDAN1:NM_138477:c.3331C>T(p.R1111*)	126	58.7	125	42.4
NP15D2229	FANCA:NM_000135:c.1108G>T(p.E370*)	98	43.9	122	57.4
NP15D2572	IFIH1:NM_022168:c.2647G>C(p.E883Q)	35	68.6	64	48.4
NP15D2572	COL6A3:NM_004369:c.6857A>C(p.N2286T)	71	47.9	98	39.8

表8 4例样本7个SNV的两次检测结果比较

实验号	突变内容	第一次检测		第二次检测
实验号	突变内容	覆盖度(×)	频率(%)	覆盖度(×)	频率(%)
MGL4-14	SMPD1:NM_000543:c.1493G>T(p.R498L)	92	32.2	130	41.9
MGL4-14	GBA:NM_000157:c.1226A>G(p.N409S)	71	59.2	113	41.1
MGL4-18	MCOLN1:NM_020533:c.406-2A>G	17	94.1	75	100
NP15D2229	CDAN1:NM_138477:c.3331C>T(p.R1111*)	126	58.7	125	42.4
NP15D2229	FANCA:NM_000135:c.1108G>T(p.E370*)	98	43.9	122	57.4
NP15D2572	IFIH1:NM_022168:c.2647G>C(p.E883Q)	35	68.6	64	48.4
NP15D2572	COL6A3:NM_004369:c.6857A>C(p.N2286T)	71	47.9	98	39.8

表9 3例样本5个Indel的两次检测结果比较

实验号	突变内容	第一次检测		第二次检测
实验号	突变内容	覆盖度(×)	频率(%)	覆盖度(×)	频率(%)
MGL4-10	HEXA:NM_000520:c.1274-1277dupTATC	39	100	73	100
R5806	TSC2:NM_000548:c.4135_4143dupTCGCAGCCC	116	43.4	200	24
	GAA:NM_000152:c.2024_2026delACA	73	42.5	109	46.2
	GAA:NM_000152:c.2312delC	64	56.2	94	43.6
NP15D2572	SLC25A13:NM_014251:c.852_855delTATG	48	34.8	61	40

表9 3例样本5个Indel的两次检测结果比较

实验号	突变内容	第一次检测		第二次检测
实验号	突变内容	覆盖度(×)	频率(%)	覆盖度(×)	频率(%)
MGL4-10	HEXA:NM_000520:c.1274-1277dupTATC	39	100	73	100
R5806	TSC2:NM_000548:c.4135_4143dupTCGCAGCCC	116	43.4	200	24
	GAA:NM_000152:c.2024_2026delACA	73	42.5	109	46.2
	GAA:NM_000152:c.2312delC	64	56.2	94	43.6
NP15D2572	SLC25A13:NM_014251:c.852_855delTATG	48	34.8	61	40

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Performance verification of IDT capture probes for human Whole-exome sequencing

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Performance verification of IDT capture probes for human Whole-exome sequencing