CMA. [DOI] /j.issn

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1 [ ] (CMA) (CNVs) CMA / 1.0cm G G Affymetrix CytoScan TM 750k CMA CMA 70 CMA 9 CNVs 3 CNVs 1 (LOH) 706 CNVs 2 (33.3% 2/6) 3 CNVs CNVs 1 (33.3% 1/3) 31 CNVs 6 (19.4% 6/31) CNVs 2 (6.5% 2/31) 30 CNVs 1 (3.3% 1/30) CNVs 1 (3.3% 1/30) CMA CMA [ ] [ ] R715.5 [ ] A [ ] (2017) [DOI] /j.issn Application value of chromosomal microarray analysis in prenatal diagnosis of lateral ventriculomegaly fetuses SONG Ting-ting, WAN Shan-ning, LI Yu, XU Ying, ZHENG Yun-yun, DANG Ying-hui, CHEN Bi-liang, ZHANG Jianfang * Department of Obstetrics and Gynecology, Xijing Hospital, Fourth Military Medical University, Xi'an , China * Corresponding author, zhangjf@fmmu.edu.cn [Abstract] Objective To analyze the genetic etiology of lateral ventriculomegaly fetal on the genome-wide level with chromosomal microarray analysis (CMA), and investigate the relationship between copy number variations (CNVs) and lateral ventriculomegaly and the application value of CMA in prenatal diagnosis of fetuses with lateral ventriculomegaly. Methods Seventy fetuses with lateral ventriculomegaly but normal or uncertain karyotype were selected and invasive prenatal diagnosis was performed in Xi Jing Hospital of the Fourth Military Medical University from Jan to Nov Microarray testing was performed using Affymetrix CytoScan TM 750k arrays and the results were analyzed according to biological information science database. The fetal development was regularly inspected, and follow up was conducted to find out the pregnancy outcome and fetal postnatal conditions. Results In 70 cases of lateral ventriculomegaly fetuses there were 9 fetuses with pathogenic copy number variations (CNVs), 3 fetuses with likely pathogenic CNVs and 1 fetus with likely pathogenic 1oss of heterozygosity (LOH). During the 70 fetuses with lateral ventriculomegaly, 2 pathogenic CNVs were detected in 6 fetuses with severe and non isolated lateral ventriculomegaly (33.3%). Pathogenic CNVs was not detected but 1 likely pathogenic CNV was detected in 3 fetuses with severe and isolated lateral ventriculomegaly (33.3%). Six pathogenic CNVs were detected in 31 mild and non isolated lateral ventriculomegaly (19.4%), and 2 likely pathogenic CNVs were also detected in these group (6.5%). One pathogenic CNV and 1 likely pathogenic CNV were detected in 30 fetuses with mild and isolated fetal lateral ventriculomegaly. Conclusions CMA can identify chromosome [ ] [ ] ( ) [ ] zhangjf@fmmu.edu.cn

2 Med J Chin PLA, Vol. 42, No. 10, October 1, abnormality microdeletion/microduplication which was unrecognizable by conventional karyotyping analysis. The application of CMA may increase the detection rate of pathogenic CNVs in fetuses with lateral ventriculomegaly, and benefit evaluation of fetal prognosis in prenatal genetic counselling. [Key words] lateral ventriculomegaly; chromosomal microarray analysis; copy number variations; prenatal diagnosis 10mm 7mm 14~40 >10mm 10~15mm >15mm ( ) [1-2] [3] [4] (copy number variations CNVs) cm G G ( ) (chromosomal microarray analysis CMA) 18~44 ( 28 ) 18~36 ( 26 ) 1.2 <15mm <15mm 15mm 15mm 70 CMA ( GE Voluson 730 GE Voluson E6 2.5~5.0MHz) ( Acuson Sequia ~5.0MHz) ( Olympus ) SNP7G CMA ( Affymetrix ) DNA 30ml CMA Qiagen (QIAamp DNA blood mini kit) DNA CMA Affymetrix CytoScan TM 750k DNA ChAS(Chrosome analysis suite) CMA kb 10Mb (loss of heterozygosity LOH) ISCA(international standards for cytogenomic arrays) NCBI(national center for biotechnology information) DECIPHER Database OMIM(online mendelian inheritance in man) CNVs CNVs CNVs CNVs CNVs CNVs [5-6] CMA 70 9 CNVs 12.8%(9/70) CNVs

3 ~28.7Mb( 1) 3 CNVs 4.3%(3/70) 2 1 CNVs 0.5~5.8Mb( 2) CMA q32.13q32.33 LOH ( 2) CMA 9 CNVs Tab.1 The pathogenic CNVs of 9 lateral ventriculomegaly fetuses detected by CMA No. Indication CMA result CNV type Size (Mb) Pregnancy outcome 1 Mild lateral ventriculomegaly, advanced age arr[crgh37] 16p11.2(28,807,417_30,190,029)x1 Deletion Mild lateral ventriculomegaly, abnormal posterior fossa arr[grch37]13q33.1q34(104,703,176_115,107,733)x1 Deletion Mild lateral ventriculomegaly, advanced age arr[grch37]13q31.2q33.2(88,867,776_106,093,135)x1 Deletion Mild lateral ventriculomegaly, posterior fossa cyst, polyhydramnios Mild lateral ventriculomegaly, abnormal cavity of septum pellucidum, ventricular septal defect 6 Hydrocephalus, spinal dysraphism 7 Mild lateral ventriculomegaly 8 Mild lateral ventriculomegaly, abnormal posterior fossa Mild lateral ventriculomegaly, abnormal cavity 9 of septum pellucidum, cerebellar vermis hypoplasia. Termination of pregnancy arr[grch37] 5q13.3q14.1(75,642,770_79,936,342)x1 Deletion 4.3 arr[grch37]5q14.3q15(84,428,488_97,070,754)x1 Deletion 12.6 arr[grch37] 4p12q13.2(47,632,643_69,435,889)x3 Duplication 21.8 arr[grch37] 4q13.2q21.23(69,541,893_86,815,623)x3 Duplication 17.3 arr[grch37]4q35.1q35.2(185,081,688_190,957,460)x1 Deletion 5.9 arr[grch37]1q21.1q21.2(145,895, ,830,830)x1 Deletion 1.9 arr[grch37]xp22.31(6,449,752-8,134,765)x2 Duplication 1.7 arr[grch37]21q22.13q22.3(39,373,647-48,093,361)x1 Deletion 24.9 arr[grch37]6p25.3p22.3(156,974-25,066,393)x3 Duplication 8.7 arr[grch37] 17p13.3(525-2,158,383)x1 Deletion 2.2 arr[grch37] 15q24.1q26.3(73,768, ,429,040)x3 Duplication 28.7 arr[grch37]22q11.1q11.21(16,888,899-20,312,661)x3 Duplication 3.4 arr[grch37]11q23.3q25(116,683, ,937,416)x3 Duplication CMA Tab.2 The likely pathogenic CNVs of 4 lateral ventriculomegaly fetuses detected by CMA Size No. Indication CMA result CNV type Inheritance Pregnancy outcome (Mb) Vascular circle, mild lateral 10 arr[grch37] 15q11.2(22,770,421_23,625,785)x1 Deletion 0.8 Maternal Loss to follow-up ventriculomegaly Mild lateral ventriculomegaly, Birth, no abnormality was 11 arr[grch37]15q11.2(22,770,421_23,288,350)x1 Deletion 0.5 Unknown oligohydramnios observed after 3 months Birth, flaccidity of neck at 3 12 Mild lateral ventriculomegaly arr[grch37]2p16.1p14(61,123,434_66,911,895)x3 Duplication 5.8 Unknown months 13 Hydrocephalus arr[grch37]14q32.13q32.33(95,377,700_107,279,475)hmz LOH 11.9 Unknown LOH. Loss of heterozygosity;. Termination of pregnancy CMA 70 9 CNVs 2 (22.2% 2/9) CNVs 1 (11.1% 1/9) 61 CNVs 7 (11.5% 7/61) CNVs 3 (4.9% 3/61) CMA 70 6 CMA CNVs 2 (33.3% 2/6) 3 CNVs CNVs 1 (33.3% 1/3) 31 CNVs 6 (19.4% 6/31) CNVs 2 (6.5% 2/31) 30 CNVs 1 (3.3% 1/30) CNVs 1 (3.3% 1/30 3) CMA CMA CNVs 1 CMA CNVs 5 CMA 2 CMA 1 CMA

4 Med J Chin PLA, Vol. 42, No. 10, October 1, Anomaly classification 3 CNVs Tab.3 Characterizations of CNVs in fetuses with different degree lateral ventriculomegaly Other abnormalities Number of fetuses Pathogenic CNVs [n(%)] Likely pathogenic CNVs [n(%)] Spinal dysraphism 3 1(33.3) 0 Non-isolated hydrocephalus (n=6) Other central nervous system anomalies 2 1(50.0) 0 Single umbilical artery Hydrocephalus (n=3) None 3 0 1(33.3) Advanced age 8 2(25.0) 0 Other central nervous system anomalies 10 2(20.0) 0 Non-isolated mild lateral ventriculomegaly (n=31) Congenital heart disease 3 0 1(33.3) Oligohydramnios/Polyhydramnios 6 0 1(16.7) Abnormal soft marker Multiple anomaly 2 2(100.0) 0 Isolated lateral ventriculomegaly (n=30) None 30 1(3.3) 1(3.3) Total 70 9(12.9) 4(5.7) B 16~ mm 1/3 <13mm 21- [7-9] 1.48 ~2.2 [10-11] CMA [12-13] [14] CNVs 11.5% CNVs 22.2% CNVs 3.3% CNVs 19.4% CNVs 3 CNVs 33.3% CMA p Mb 28 OMIM OMIM 16p11.2 (OMIM ) Decipher ISCA [15-16] CMA q33.1q Mb q31.2q Mb 1.4Mb OMIM 13q33.1q34 EEFNB2 ARGLU1 LIG4 ARHGEF7 SOX1 29 OMIM 13q31.2q33.2 GPC5 ZIC2 PCCA FGF14 40 OMIM ISCA NCBI Decipher OMIM Dandy- Walker [17] 4 5 5q13.3q14.1 5q14.3q Mb NR2F1 MEF2C 47 OMIM NR2F1 MEF2C

5 ISCA NCBI Decipher OMIM MEF2C p12q13.2 4q13.2q Mb 4q35.1q Mb ISCA NCBI Decipher OMIM [18] B 1.1cm 6 1 1q21.1q Mb X Xp Mb 1q21.1 X Xp Mb HDHD1 STS VCX PNPLA4 4 OMIM ISCA NCBI Decipher OMIM [19] [20] 7 6 6p25.3p Mb 21 21q22.13q Mb CNVs 77 OMIM ISCA NCBI Decipher OMIM [21] FOXC1 Dandy-Walker [22] 74 OMIM p Mb 15 15q24.1q Mb CRK PRPF8 HIC1 YWHAE 30 OMIM YWHAE [23] CPEB1 NTRK3 FURIN NR2F2 IGF1R 143 OMIM Decipher 15q26 [24] q11.1q Mb 11 11q23.3q Mb 22 22q11.2 ISCA NCBI Decipher OMIM OMIM ISCA NCBI Decipher OMIM [25] CMA CMA 2 15q q Mb q kb ISCA NCBI Decipher OMIM CYFIP1 NIPA1 NIPA2 TUBGCP5 [26-27] CNVs CMA CMA 1 15q q CMA B p16.1p Mb XPO1 CCT4 EHBP1 22 OMIM ISCA NCBI Decipher OMIM Decipher 2 ( ) q32.13q Mb RTL1 DLK1 Temple [28]

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