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J Zhejiang Univ (Med Sci)  2019, Vol. 48 Issue (4): 420-428    DOI: 10.3785/j.issn.1008-9292.2019.08.12
    
Application of single nucleotide polymorphism microarray in clinical diagnosis of intellectual disability or retardation
HU Junjie(),QIAN Yeqing,SUN Yixi,YU Jialing,LUO Yuqin,DONG Minyue*()
Key Laboratory of Reproductive Genetics, Ministry of Education, Department of Reproductive Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
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Abstract  

Objective: To assess the clinical application of single nucleotide polymorphism microarray (SNP array) in patients with intellectual disability/developmental delay(ID/DD). Methods: SNP array was performed to detect genome-wide DNA copy number variants (CNVs) for 145 patients with ID/DD in Women's Hospital, Zhejiang University School of Medicine from January 2013 to June 2018. The CNVs were analyzed by CHAS software and related databases. Results: Among 145 patients, pathogenic chromosomal abnormalities were detected in 32 cases, including 26 cases of pathogenic CNVs and 6 cases of likely pathogenic CNVs. Meanwhile, 18 cases of uncertain clinical significance and 14 cases of likely benign were identified, no significant abnormalities were found in 81 cases (including benign). Conclusion: SNP array is effective for detecting chromosomal abnormalities in patients with ID/DD with high efficiency and resolution.



Key wordsIntellectual disability/genetics      Developmental disabilities/genetics      Chromosomes      Microchip analytical procedures      Polymorphism, single nucleotide     
Received: 01 April 2019      Published: 30 October 2019
CLC:  R394.3  
Corresponding Authors: DONG Minyue     E-mail: hujunjie@zju.edu.cn;dongmy@zju.edu.cn
Cite this article:

HU Junjie,QIAN Yeqing,SUN Yixi,YU Jialing,LUO Yuqin,DONG Minyue. Application of single nucleotide polymorphism microarray in clinical diagnosis of intellectual disability or retardation. J Zhejiang Univ (Med Sci), 2019, 48(4): 420-428.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2019.08.12     OR     http://www.zjujournals.com/med/Y2019/V48/I4/420


单核苷酸多态性微阵列分析对智力障碍和发育迟缓的遗传学诊断价值

目的: 评估单核苷酸多态性微阵列(SNP array)分析在智力障碍/发育迟缓(ID/DD)遗传学诊断中的应用价值。方法: 以2013年1月至2018年6月在浙江大学医学院附属妇产科医院因ID/DD行SNP array的145例患者为研究对象,采用CHAS软件与多种数据库对染色体拷贝数变异(CNV)进行分析。结果: 145例ID/DD患者通过SNP array技术发现致病性CNV 26例,可能致病CNV 6例,意义不明18例,可能良性14例,未见明显异常(包含良性)81例。结论: SNP array技术是一种高效和特异的遗传学分析技术,适用于ID/DD的遗传学病因诊断。


关键词: 智力障碍/遗传学,  发育障碍/遗传学,  染色体,  芯片分析技术,  多态性, 单核苷酸 
Fig 1 Interpretation process of the results of single nucleotide polymorphism microarray
序号 性别 年龄 病史 检测结果arr[hg19] 片段长度(kb) 结果判读及依据 ClinGen评分 pLI指数
“—”:无相关数据.ID:智力障碍;DD:发育迟缓;IQ:智商指数;AD:常染色体显性遗传;XLR:X连锁隐性遗传;PLI:功能丧失不容忍指数.
1 4个月 DD、足月小样儿 1p36.33p36.31(849 466~6 927 948)×1 6078 致病性,CAMTA1(611501)AD,位于1p36微缺失综合征 3 1.0
2 25岁 ID、本人面部畸形,前胎先天性心脏病 1p36.32p36.23(5 278 785~8 507 731)×1 3229 致病性,CAMTA1(611501)AD,位于1p36微缺失综合征 3 1.0
3 4岁 ID/DD 2p25.3p24.3(12 770~15 590 659)×3 15 578 致病性,>10 Mb
15q26.3(100 597 165~102 429 112)×1 1831 临床意义未明,位于15q26增生综合征
4 30岁 ID 2p25.3p24.3(12 770~15 590 659)×3 15 578 致病性,>10 Mb
15q26.3(100 597 165~102 429 112)×11832临床意义未明,位于15q26增生综合征
5 7岁 ID、出生时脸部有赘生物,手精细运动不灵活 3p26.3p25.3(61 891~9 706 654)×1 9645 致病性,SETD5(615743)AD 3 1.0
7q36.1(149 552 532~150 150 057)×3598临床意义未明
6 22岁 ID/DD、面部畸形 4q28.3q31.21(133 624 276~143 279 820)×1 9656 致病性,NAA15(608000)AD 2 0.999
7 5岁 ID/DD、唇腭裂 4q31.3q34.1(154 700 857~174 858 619)×1 20 158 致病性,>10 Mb
8 1岁 DD、五官畸形 4q34.1q35.2(175 368 718~190 957 473)×1 15 589 致病性,>10 Mb
5q15q23.1(96 373 240~118 982 484)×2 hmz22 609杂合性缺失
9 29岁 ID、肾脏疾病等 7q11.23(72 834 405~74 141 493)×1 1307 致病性,Williams-Beuren综合征 3
10 2岁 ID/DD 6p23p22.3(14 041 412~15 283 501)×3 1242 临床意义未明
7q36.2q36.3(153 231 421~159 119 707)×15888致病性,DPP6(612956)AD30.968
11 3岁 DD、先天性心脏病 8p23.1(8 093 065~11 881 742)×3 2789 致病性,8p23.1重复综合征 3
22q11.21(18 916 827~21 464 763)×12548致病性,22q11.2缺失综合征3
12 6岁 ID、母亲为平衡易位携带者,46XXt(9;14)(q22;p12) 9p24.3(203 861~86 366 350)×3 86 162 致病性,>10 Mb
13 36岁 ID、IQ 50+ 10q22.3q23.2(81 457 752~89 027 024)×1 7569 致病性,10q22-q23缺失综合征 3
14 6岁 ID、先天性失明 11p14.1p12(30 808 717~39 258 015)×1 8449 致病性,WAGR 11p13缺失综合征 3
15 7岁 ID、脑白质发育不良 7p22.2(3 703 104~4 241 241)×1 538 临床意义未明
11q23.3q24.3(119 106 833~129 224 378)×110 118致病性,>10 Mb
16 39岁 ID 12p13.33p13.32(296 244~5 013 540)×1 4717 致病性,12p13.33微缺失综合征
17 6岁 DD 47XY+mar[66.7%]/46XY[33.3%] 13q11q13.3(19 436 286~38 290 901)×2~3 18 854 致病性,>10 Mb
18 27岁 ID 14q11.2q12(20 511 672~31 130 390)×2~3 10 619 致病性,>10 Mb
19 3岁 DD、脑发育不良、癫痫 15q11.2q13.1(23 620 191~28 534 359)×1 4914 致病性,Prader-Willi/Angelman综合征 3
20 8岁 ID、不会讲话、47XY+mar Yq11.223q11.23(24 988 143~28 423 925)×215q11.2q13.1(22 770 421~28 644 578)×4 34355874 可能良性致病性,Prader-Willi/Angelman综合征 —3
21 2岁 DD,不会说话不会走,听力降低 16p13.3(85 880~1 028 246)×1 942 致病性,红细胞异常-智力障碍综合征
16p13.3p13.13(1 066 252~11 249 660)×310 183致病性,>10 Mb
22 13岁 ID,尿道下裂,先心室间隔缺失,听力异常 9p24.3p24.1(203 861~7 738 229)×1 7534 可能致病
16q23.1q24.3(76 494 902~90 155 062)×313 660致病性,>10 Mb
23 7岁 DD 14q31.3(88 056 554~88 641 038)×3 585 临床意义未明
17p12p11.1(14 078 263~22 227 062)×38149致病性,Charcot-Marie-Tooth综合征1A型17p11.2重复综合征3
1A型17p11.2重复综合征3
24 21岁 ID 18p11.32p11.21(136 226~14 363 631)×3 14 227 致病性,>10 Mb
21q11.2(15 006 457~15 833 827)×3827临床意义未明
25 26岁 ID,伴糖尿病 22q11.21q11.22(21 465 661~22 962 196)×1 1497 致病性,22q11.2远端缺失综合征 3
26 6岁 ID/DD,大伯一女儿口齿不清,多动症,智商低 Xq22.1q22.2(102 465 091~103 577 991)×2 1113 致病性,佩梅病,PLP1(300401)XLR 3 0.903
Tab 1 Clinical data and single nucleotide polymorphism microarray results of 26 patients with pathogenic copy number variations
序号 性别 年龄 病史 检测结果arr[hg19] 片段长度
(kb)
结果判读及依据
ID:智力障碍;DD:发育迟缓;PIMD:PubMed唯一标识码;AD:常染色体显性遗传.
27 15个月 DD 1q41q42.13(223 269 645~228 173 392)×1 4904 可能致病,PMID:271840082435707625900767
28 5岁 DD 7p14.1p12.3(38 877 764~46 362 179)×1 7484 可能致病,PMID:1650914,CDK13(603309)AD
29 22岁 ID 8p23.3p23.1(158 048~9 647 023)×1 9489 可能致病,与8p23.1缺失综合征大部分重叠
30 6岁 ID 17p13.2p13.3(2 582 247~3 412 325)×3 830 可能致病,PMID:1913695021595003,位于Miller-Dieker综合征区域
31 10岁 ID 4p15.33(11 778 523~12 875 904)×3
17q12(34 822 465~36 307 773)×1
1097
1485
可能良性,4p15.33遗传自父亲
可能致病,快速循环型情感障碍综合征HNF1B(189907)AD
32 14岁 ID/DD、癫痫、步态不稳 18p11.32p11.31(136 226~6 149 134)×1
18q23(75 302 204~78 014 123)×3
6013
2712
可能致病,PMID:26278570,TGIF1(602630)AD
临床意义未明
Tab 2 Clinical data and single nucleotide polymorphism microarray results of 6 patients with likely pathogenic copy number variations
序号 性别 年龄(岁) 病史 检测结果arr[hg19] 片段长度(kb) 结果判读及依据
ID:智力障碍;DD:发育迟缓;IQ:智商指数;DGV No.:基因组变异数据库记录例数;AR:常染色体隐性遗传.
33 24 ID 1q21.1(145 617 348~145 888 926)×1 272 临床意义未明
34 26 本人与弟弟均是ID 1q31.1(189 320 335~189 537 683)×1
8q22.2(100 273 863~100 564 876)×1
291 可能良性,DGV6
临床意义未明,DGV1,VPS13B(607817)AR
35 23 ID,出生时有窒息史、出生体质量2.4 kg,走路不稳 3p24.1p22.3(30 566 655~36 027 917)×1 5461 临床意义未明
36 11 ID 6q15q16.1(91 572 709~94 390 667)×1 2818 临床意义未明
37 6 ID,IQ 60+,自闭症 6q22.1(116 977 968~117 609 892)×3 632 临床意义未明
38 1 DD 6q27(167 595 151~168 224 287)×3 629 临床意义未明
39 12 ID 7q21.11(82 712 935~83 043 602)×3 331 临床意义未明
40 5 ID,头颅增大 9p23(11 734 432~12 074 149)×1 340 临床意义未明
41 27 ID,IQ 50 11q14.1q14.3(80 257 567~88 934 583)×1 8677 临床意义未明
42 10 ID,IQ 60,先天性心脏病,染色体正常 12p13.33p13.31(173 786~6 417 126)×3
17q25.3(76 102 160~80 396 283)×3
17q25.3(80 396 463~81 041 938)×1
6243
4294
645
临床意义未明
临床意义未明
临床意义未明
43 22 ID,月经不调,外伤后出现“脑水肿” 12q15q21.1(70 339 049~75 264 408)×1 4925 临床意义未明
44 32 ID 15q11.2(22 770 421~23 290 819)×3/DGV 520 临床意义未明
45 37 ID,月经失调,祖父母近亲结婚 16q23.1(76 425 154~77 171 390)×3 746 临床意义未明
46 7 DD 21q11.2(15 006 457~15 713 941)×3 707 临床意义未明
47 11 ID,先天无脑回,祖父母近亲结婚,姑妈为聋哑患者 Xp11.3(44 298 687~44 947 473)×3
Xp11.23p11.22(49 174 228~50 026 412)×3
64
852
临床意义未明临床意义未明
48 4 ID,脑积水,视网膜病变 Xp22.33(1 024 439~1 844 417)×1
Xq13.1(68 051 752~68 894 767)×2
820
843
临床意义未明临床意义未明
49 35 ID,面容呆滞 Xq12(65 377 222~66 451 783)×2 1075 临床意义未明
50 11 ID Xq25(123 508 622~124 030 958)×2
6q26(163 008 514~163 259 223)×1
522
251
临床意义未明
临床意义未明
Tab 3 Clinical data and single nucleotide polymorphism microarray results of 18 patients with uncertain clinical significance copy number variations
序号 性别 年龄
(岁)
病史 检测结果arr[hg19] 片段长度
(kb)
结果判读及依据
ID:智力障碍;DD:发育迟缓;IQ:智商指数;DGV No.:基因组变异数据库记录例数;OMIM:在线人类孟德尔遗传数据库.
51 30 本人和女儿均为ID 1p21.1(106 034 937~106 269 061)×1 234 可能良性,DGV1,不包含OMIM基因
52 4 ID/DD,IQ 64 1q31.1(188 704 364~189 128 944)×1 425 可能良性,本地数据库多例正常人群外周血记录
53 7 ID,法洛四联症、马蹄肾、面谱人 2q21.1(131 477 947~131 984 527)×1/DGV6例 507 可能良性,DGV6
54 10 ID,IQ<40 4q35.2(187 922 671~188 948 985)×3 1026 可能良性,DGV2,本地数据库多例正常人外周血记录
55 6 ID 5p12p11(45 676 469~46 389 339)×3 713 可能良性,遗传自正常表型母亲
56 24 ID 6q26(162 358 261~162 612 365)×/DGV4例 254 可能良性,DGV4
57 6 ID,至今不会说话,MR提示两侧顶叶皮层及右侧基底节异常信号,脑回大,脑沟少,考虑先天性发育不全,巨脑回可能。患者有一舅舅,存在类似症状,但程度较轻 9p21.3(21 448 447~21 693 490)×1 245 可能良性,遗传自正常表型父亲
58 5 DD 10p15.3(1 342 958~1 868 636)×3
17p11.2p11.1(21 552 185~22 261 792)×3
526
710
可能良性,DGV2,表型正常的弟弟有一致区段
可能良性,DGV2
59 11 ID,特殊面容 16p11.2(28 689 085~29 051 191)×1 362 可能良性,遗传自正常表型父亲
60 8 DD,精神发育迟滞,染色体正常 Xp22.32p22.31(5 970 504~6 075 215)×3 105 可能良性,遗传自正常表型父亲
61 2 ID,运动发育迟缓 Xp22.33(565 815~1 223 445)×1 658 可能良性,遗传自正常表型母亲,弟弟芯片结果一致
62 13 ID,自闭症 Xq13.1(68 954 896~69 552 681)×3 598 可能良性,遗传自正常表型母亲
63 2 ID,听力障碍 Xq28(154 941 868~155 233 731)×1 292 可能良性,遗传自正常表型父亲
64 7 ID Xq28(148 731 893~149 549 959)×2 818 可能良性,遗传自正常表型母亲
Tab 4 Clinical data and single nucleotide polymorphism microarray results of 14 patients with likely benign copy number variations
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