染色体微阵列技术在孕期羊水过多遗传病因诊断中的应用

doi:10.12280/gjszjk.20240232

摘要/Abstract

摘要：

目的： 利用染色体微阵列技术（chromosomal microarray analysis，CMA）分析羊水过多的遗传病因。方法： 收集2017年1月—2023年4月泉州市妇幼保健院·儿童医院产前超声提示羊水过多的病例共112例。所有纳入研究病例均行染色体核型分析及CMA检测。并根据超声检测结果进行分组研究，其中单纯性羊水过多组共16例，羊水过多合并超声结构异常组27例，羊水过多合并超声软指标异常组69例。结果： 染色体核型分析共检出4例染色体非整倍体、1例非整倍体染色体嵌合和1例染色体结构异常嵌合，异常检出率为5.36%（6/112）。CMA分析检出了染色体核型分析检出的所有染色体变异，同时检出4例致病性或可能致病性拷贝数变异，额外检出率为3.57%（4/112）。此外，单纯性羊水过多组、合并超声软指标异常组和合并超声结构异常组间染色体异常检出率差异无统计学意义（P=0.571）。结论： 羊水过多可能与胎儿染色体异常有关，染色体核型分析联合CMA技术有益于检出更多致病性拷贝数变异。因此，羊水过多胎儿的遗传病因分析及预后评估中建议应用染色体核型分析联合CMA检测。

关键词: 羊水过多, 染色体, 微阵列分析, 核型分析, DNA拷贝数变异

Abstract:

Objective: To explore the genetic diagnosis of fetuses with polyhydramnios using chromosomal microarray analysis (CMA). Methods: A total of 112 cases of the polyhydramnios diagnosed by prenatal ultrasound at Quanzhou Women′s and Children′s Hospital from January 2017 to April 2023 were collected. All of the enrolled subjects underwent chromosomal karyotype and CMA analysis. According to the results of ultrasound, the subjects were divided into three groups, the isolated polyhydramnios group (16 cases), the group of polyhydramnios with ultrasound structural abnormalities (27 cases), and the group of polyhydramnios with abnormal ultrasound soft markers (69 cases). Results: Chromosome karyotype analysis found 4 cases of chromosomal aneuploidy, 1 case of aneuploid chromosomal chimerism, and 1 case of chromosomal structural abnormality chimerism, with an abnormal detection rate of 5.36% (6/112). CMA detected all chromosomal abnormalities, and 4 additional cases of pathogenic or likely pathogenic copy number variants, with an additional detection rate of 3.57% (4/112). In addition, there was no statistical difference in the positive detection rate among three groups (P=0.571). Conclusions: Pregnancy with polyhydramnios may be related to fetal chromosomal abnormalities. The chromosome karyotype analysis combined with CMA technique is beneficial to detect more pathogenic copy number variants. Therefore, the chromosome karyotype analysis combined with CMA detection can be recommended in the genetic etiology analysis and prognosis evaluation of fetuses with polyhydramnios.

Key words: Polyhydramnios, Chromosomes, Microarray analysis, Karyotyping, DNA copy number variations

王俊育, 陈文莉, 吴荣泉, 江矞颖, 庄建龙. 染色体微阵列技术在孕期羊水过多遗传病因诊断中的应用[J]. 国际生殖健康/计划生育杂志, 2024, 43(5): 384-389.

WANG Jun-yu, CHEN Wen-li, WU Rong-quan, JIANG Yu-ying, ZHUANG Jian-long. Application of Chromosome Microarray Technology in Genetic Etiology Diagnosis of Fetuses with Polyhydramnios[J]. Journal of International Reproductive Health/Family Planning, 2024, 43(5): 384-389.

图/表 6

参考文献 18

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序号	CMA结果	片段大小	来源	致病性判读	超声结果	妊娠结局随访
1	arr[GRCh37]16q11.2(46,503,192- 46,925,074)×3,17q11.2(29,075, 556-30,298,421)×1	421.8 kb；1.2 Mb	新发	VOUS；致病	羊水过多	终止妊娠
2	arr[GRCh37]12p13.33q12(173, 786-40,380,906)×3-4	40.2 Mb	/	致病	羊水过多；肠道强回声；肾盂扩张	终止妊娠
3	arr[GRCh37]Yq11.223q11.23 (24,804,873-28,398,102)×0	3.5 Mb	新发	可能致病	羊水过多；肾盂扩张	继续妊娠
4	arr[GRCh37]5q31.2q31.3 (137,753,256-144,316,905)×1	6.5 Mb	/	致病	羊水过多；胎儿宫内发育迟缓；单脐动脉	终止妊娠
5	arr[GRCh37]17q12(34,822,466- 36,307,773)×1	1.4 Mb	/	致病	羊水过多；心脏强回声；永存左上腔静脉；双肾实质回声增强	终止妊娠

序号	CMA结果	片段大小	来源	致病性判读	超声结果	妊娠结局随访
1	arr[GRCh37]16q11.2(46,503,192- 46,925,074)×3,17q11.2(29,075, 556-30,298,421)×1	421.8 kb；1.2 Mb	新发	VOUS；致病	羊水过多	终止妊娠
2	arr[GRCh37]12p13.33q12(173, 786-40,380,906)×3-4	40.2 Mb	/	致病	羊水过多；肠道强回声；肾盂扩张	终止妊娠
3	arr[GRCh37]Yq11.223q11.23 (24,804,873-28,398,102)×0	3.5 Mb	新发	可能致病	羊水过多；肾盂扩张	继续妊娠
4	arr[GRCh37]5q31.2q31.3 (137,753,256-144,316,905)×1	6.5 Mb	/	致病	羊水过多；胎儿宫内发育迟缓；单脐动脉	终止妊娠
5	arr[GRCh37]17q12(34,822,466- 36,307,773)×1	1.4 Mb	/	致病	羊水过多；心脏强回声；永存左上腔静脉；双肾实质回声增强	终止妊娠

序号	CMA结果	片段大小	来源	致病性判读	超声结果	妊娠结局随访
1	arrGRCh37]10q11.23q21.3(50,947, 506-65,406,161)×2 hmz	14.4 Mb	/	ROH	右肾重复肾并肾盂扩张；双输尿管之一迂曲扩张及末端囊肿形成，羊水过多	继续妊娠
2	arr[GRCh37]10q23.1(85,729,937- 87,756,822)×1	2.0 Mb	/	VOUS	NT：2.9 mm；羊水过多	失访
3	arr[GRCh37]2q12.3(108,513,707- 109,108,460)×1,17q11.2(28,964, 044-29,428,599)×3	594.7 kb；464.5 kb	/	VOUS	羊水过多；鼻骨发育不良/缺失；先天性心脏病；右锁骨下动脉迷走	继续妊娠
4	arr[GRCh37]3q26.2(168,247,002- 169,240,691)×3	993.6 kb	遗传自母亲	VOUS	羊水过多；NT：2.7 mm；心脏强回声；肾盂扩张	继续妊娠
5	arr[GRCh37]3p12.2(81,619,653- 81,794,249)×1	174.5 kb	遗传自父亲	VOUS	羊水过多；后颅窝池增宽	继续妊娠
6	arr[GRCh37]Xp11.3(42,928,705- 43,584,968)×2	656.2 kb	/	VOUS	羊水过多	终止妊娠
7	arr[GRCh37]2q13(110,498,142- 110,980,295)×1	482.1 kb	/	VOUS	羊水过多；侧脑室增宽：左侧1.08 cm；心脏强回声；肠道强回声	继续妊娠
8	arr[GRCh37](4)×2 hmz	/	/	UPD	羊水过多；胎儿右位主动脉弓并左位导管；冠状静脉窦扩张并左上腔静脉残存	失访
9	arr[GRCh37]8p22p21.3(18,146, 335-19,382,611)×3	1.2 Mb	/	VOUS	胎儿腹腔积液；右心偏大；永存左上腔；羊水过多；心脏强回声；三尖瓣返流	失访

序号	CMA结果	片段大小	来源	致病性判读	超声结果	妊娠结局随访
1	arrGRCh37]10q11.23q21.3(50,947, 506-65,406,161)×2 hmz	14.4 Mb	/	ROH	右肾重复肾并肾盂扩张；双输尿管之一迂曲扩张及末端囊肿形成，羊水过多	继续妊娠
2	arr[GRCh37]10q23.1(85,729,937- 87,756,822)×1	2.0 Mb	/	VOUS	NT：2.9 mm；羊水过多	失访
3	arr[GRCh37]2q12.3(108,513,707- 109,108,460)×1,17q11.2(28,964, 044-29,428,599)×3	594.7 kb；464.5 kb	/	VOUS	羊水过多；鼻骨发育不良/缺失；先天性心脏病；右锁骨下动脉迷走	继续妊娠
4	arr[GRCh37]3q26.2(168,247,002- 169,240,691)×3	993.6 kb	遗传自母亲	VOUS	羊水过多；NT：2.7 mm；心脏强回声；肾盂扩张	继续妊娠
5	arr[GRCh37]3p12.2(81,619,653- 81,794,249)×1	174.5 kb	遗传自父亲	VOUS	羊水过多；后颅窝池增宽	继续妊娠
6	arr[GRCh37]Xp11.3(42,928,705- 43,584,968)×2	656.2 kb	/	VOUS	羊水过多	终止妊娠
7	arr[GRCh37]2q13(110,498,142- 110,980,295)×1	482.1 kb	/	VOUS	羊水过多；侧脑室增宽：左侧1.08 cm；心脏强回声；肠道强回声	继续妊娠
8	arr[GRCh37](4)×2 hmz	/	/	UPD	羊水过多；胎儿右位主动脉弓并左位导管；冠状静脉窦扩张并左上腔静脉残存	失访
9	arr[GRCh37]8p22p21.3(18,146, 335-19,382,611)×3	1.2 Mb	/	VOUS	胎儿腹腔积液；右心偏大；永存左上腔；羊水过多；心脏强回声；三尖瓣返流	失访

组别	n	非整倍体	嵌合体	结构异常	p/lpCNVs	染色体异常检出率（%）	pCNVs检出率（%）	阳性检出率（%）
单纯性羊水过多组	16	0	1	0	1	6.25	6.25	12.50
合并超声结构异常组	27	1	0	0	0	3.70	0.00	3.70
合并超声软指标异常组	69	3	0	1	3	5.80	4.35	10.15
合计	112	4	1	1	4	5.36	3.57	8.93