Application of CNV-seq in the genetic detection of elevated fetal nuchal translucency

doi:10.3969/j.issn.1673-8640.2021.09.014

Abstract

Abstract:

Objective To investigate the application role of whole-genome copy number variation（CNV） sequencing （CNV-seq） in the genetic detection of elevated fetal nuchal translucency（NT）. Methods The clinical data of 110 fetuses NT≥3.0 mm in the first trimester of pregnancy were collected and analyzed. The fetal villi or amniotic fluid samples with NT thickening were taken for karyotype analysis and CNV-seq. The pathogenicity of CNV was analyzed by querying the common database resources such as ClinGen,ClinVar,DECIPHER,OMIM,UCSC,the database of genomic variants（DGV） and PubMed. Results Among the 110 cases,26 cases were abnormal in karyotype,and the detection rate was 23.6%. Among them,25 cases were abnormal in aneuploidy,and 1 case was abnormal in small supernumerary marker chromosome（sSMC）（chimeric ratio was 20%）. CNV-seq detected 36 abnormal cases and 10 cases of microdeletions/microduplications（7 cases of unknown clinical significance and 3 cases of suspected pathogenic variations）that could not be detected by karyotype analysis,and defined the origin of one sSMC derived from 12 p13.33-p11.1（34.66 Mb,chimeric ratio was 20%）. Conclusions CNV-seq can detect the abnormal chromosome submicrostructure which is difficult to be finded by karyotype analysis,and it can define the source and fragment size of marker chromosome,which is helpful to improve the diagnosis of the genetic cause of the fetuses with NT thickening.

Key words: Whole-genome copy number variation sequencing, Nuchal translucency, Chromosome variation, Chromosome submicrostructure abnormality, Small supernumerary marker chromosome

CLC Number:

R446.7

LUO Yinghua, LIU Bailing, HUANG Jiwei, WANG Yuanliu, ZENG Dingyuan, TANG Ning. Application of CNV-seq in the genetic detection of elevated fetal nuchal translucency[J]. Laboratory Medicine, 2021, 36(9): 951-956.

Figures/Tables 3

References 15

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NT	例数	染色体数目异常/例	CNV异常/例	合计/ [例（%）]
3.0~3.4 mm	44	9	3	12（27.3）
3.5~4.4 mm	37	6	6	12（32.4）
4.5~6.4 mm	20	6	1	7（35.0）
>6.4 mm	9	5	0	5（55.6）

NT	例数	染色体数目异常/例	CNV异常/例	合计/ [例（%）]
3.0~3.4 mm	44	9	3	12（27.3）
3.5~4.4 mm	37	6	6	12（32.4）
4.5~6.4 mm	20	6	1	7（35.0）
>6.4 mm	9	5	0	5（55.6）

样本序号	核型	CNV-seq	片段长度/Mb	基因	致病性	妊娠结局
1	46,XN	seq[hg19]del（12）（q21.1q21.2）chr12：g.73240001_76520000del	3.28	NAP1L1、LOC100507377、KRR1、GLIPR1L2、GLIPR1、KCNC2、CAPS2、GLIPR1L1、PHLDA1、ATXN7L3B、LOC101928137	可疑致病性	引产
2	46,XN	seq[hg19]del（15）（q11.2）chr15：g.22760000_23100000del	0.34	TUBGCP5、NIPA1、LOC283683、CYFIP1、NIPA2	可疑致病性	顺产
3	46,XN	seq[hg19]dup（22）（q11.21）chr22：g.18940001_21800000dup	2.86	22q11微重复综合征	可疑致病性	引产
4	46,XN	seq[hg19]del（8）（q21.12q21.13）chr8：g.79740001_84320000del	4.58	SNX16、SLC10A5、FABP5、FABP4、LOC101927067、LINC01419、PMP2、MRPS28、PAG1、MIR5708、STMN2、FABP12、ZFAND1、HEY1、ZBTB10、LOC101927040、TPD52、IMPA1、ZNF704、FABP9、CHMP4C	临床意义未明	剖宫产
5	46,XN	seq[hg19]dup（8）（q12.1q12.3）chr8：g.61580001_63240000dup	1.66	ASPH、MIR4470、NKAIN3、CLVS1、CHD7、LOC100130298	临床意义未明	引产
6	46,XN	seq[hg19]dup（5）（q23.2）chr5：g.124520001_125920000dup	1.40	LOC101927421、LOC101927460、GRAMD3、LOC102546228、ALDH7A1、LOC101927488	临床意义未明	引产
7	46,XN	seq[hg19]dup（10）（p15.3p15.2）chr10：g.1200001_3120000dup	1.92	ADARB2-AS1、LINC00200、ADARB2、LINC00701、MIR6072、LINC00700、PFKP	临床意义未明	顺产
样本序号	核型	CNV-seq	片段长度/Mb	基因	致病性	妊娠结局
8	46,XN	seq[hg19]dup（2）（q32.3）chr2：g.193940001_195080000dup	1.14	无基因	临床意义未明	剖宫产
9	46,XN	seq[hg19]dup（X）（p11.21）chrX：g.55460001_56460000dup	1.00	MIR4536-1、KLF8、RRAGB、FOXR2、MIR4536-2、USP51、MAGEH1	临床意义未明	剖宫产
10	46,XN	seq[hg19]dup（2）（q21.2q21.3）chr2：g.134040001_135440000dup	1.40	TMEM163、MIR7853、NCKAP5、MIR3679、MGAT5、LOC101928161	临床意义未明	顺产

样本序号	核型	CNV-seq	片段长度/Mb	基因	致病性	妊娠结局
1	46,XN	seq[hg19]del（12）（q21.1q21.2）chr12：g.73240001_76520000del	3.28	NAP1L1、LOC100507377、KRR1、GLIPR1L2、GLIPR1、KCNC2、CAPS2、GLIPR1L1、PHLDA1、ATXN7L3B、LOC101928137	可疑致病性	引产
2	46,XN	seq[hg19]del（15）（q11.2）chr15：g.22760000_23100000del	0.34	TUBGCP5、NIPA1、LOC283683、CYFIP1、NIPA2	可疑致病性	顺产
3	46,XN	seq[hg19]dup（22）（q11.21）chr22：g.18940001_21800000dup	2.86	22q11微重复综合征	可疑致病性	引产
4	46,XN	seq[hg19]del（8）（q21.12q21.13）chr8：g.79740001_84320000del	4.58	SNX16、SLC10A5、FABP5、FABP4、LOC101927067、LINC01419、PMP2、MRPS28、PAG1、MIR5708、STMN2、FABP12、ZFAND1、HEY1、ZBTB10、LOC101927040、TPD52、IMPA1、ZNF704、FABP9、CHMP4C	临床意义未明	剖宫产
5	46,XN	seq[hg19]dup（8）（q12.1q12.3）chr8：g.61580001_63240000dup	1.66	ASPH、MIR4470、NKAIN3、CLVS1、CHD7、LOC100130298	临床意义未明	引产
6	46,XN	seq[hg19]dup（5）（q23.2）chr5：g.124520001_125920000dup	1.40	LOC101927421、LOC101927460、GRAMD3、LOC102546228、ALDH7A1、LOC101927488	临床意义未明	引产
7	46,XN	seq[hg19]dup（10）（p15.3p15.2）chr10：g.1200001_3120000dup	1.92	ADARB2-AS1、LINC00200、ADARB2、LINC00701、MIR6072、LINC00700、PFKP	临床意义未明	顺产
样本序号	核型	CNV-seq	片段长度/Mb	基因	致病性	妊娠结局
8	46,XN	seq[hg19]dup（2）（q32.3）chr2：g.193940001_195080000dup	1.14	无基因	临床意义未明	剖宫产
9	46,XN	seq[hg19]dup（X）（p11.21）chrX：g.55460001_56460000dup	1.00	MIR4536-1、KLF8、RRAGB、FOXR2、MIR4536-2、USP51、MAGEH1	临床意义未明	剖宫产
10	46,XN	seq[hg19]dup（2）（q21.2q21.3）chr2：g.134040001_135440000dup	1.40	TMEM163、MIR7853、NCKAP5、MIR3679、MGAT5、LOC101928161	临床意义未明	顺产