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中华产科急救电子杂志

中华产科急救电子杂志 ›› 2022, Vol. 11 ›› Issue (01) : 38 -45. doi: 10.3877/cma.j.issn.2095-3259.2022.01.009

论著

非免疫性胎儿水肿综合征的遗传学因素及妊娠结局分析
丁丽娜1, 高智霖2, 张慧敏2, 何文智2, 李少英2, 陈敏2, 陈菲2, 翦薇2, 李南2, 谢亦农2, 李志华2,†()   
  1. 1. 广州医科大学附属第三医院妇产科　广州重症孕产妇救治中心　广东省产科重大疾病重点实验室　广东省普通高校生殖与遗传重点实验室　510150；广东省，东莞市松山湖中心医院产科　南方医科大学附属东莞石龙人民医院　523000
    2. 广州医科大学附属第三医院妇产科　广州重症孕产妇救治中心　广东省产科重大疾病重点实验室　广东省普通高校生殖与遗传重点实验室　510150
  • 收稿日期:2021-06-30 出版日期:2022-02-18
  • 通信作者: 李志华
  • 基金资助:
    广东省自然科学基金(2018A0303130298)

Genetic etiology and pregnancy outcome of non-immune fetal edema syndrome: a Chinese cohort study

Lina Ding1, Zhilin Gao2, Huimin Zhang2, Wenzhi He2, Shaoying Li2, Min Chen2, Fei Chen2, Wei Jian2, Nan Li2, Yinong Xie2, Zhihua Li2,†()   

  1. 1. Obstetric of Gynecology and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical Center for Critical Pregnant Women, Guangdong Province Key Laboratory of Major Obstetric Diseases, Key Laboratory for Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou 510150, China; Deportment of Obstetrics, Central Hospital of Dongguan, Affiliated Dongguan Shilong People′s Hospital of Southorn Medical University, Dongguan 523000, China
    2. Obstetric of Gynecology and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical Center for Critical Pregnant Women, Guangdong Province Key Laboratory of Major Obstetric Diseases, Key Laboratory for Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou 510150, China
  • Received:2021-06-30 Published:2022-02-18
  • Corresponding author: Zhihua Li
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引用本文：

丁丽娜, 高智霖, 张慧敏, 何文智, 李少英, 陈敏, 陈菲, 翦薇, 李南, 谢亦农, 李志华. 非免疫性胎儿水肿综合征的遗传学因素及妊娠结局分析[J]. 中华产科急救电子杂志, 2022, 11(01): 38-45.

Lina Ding, Zhilin Gao, Huimin Zhang, Wenzhi He, Shaoying Li, Min Chen, Fei Chen, Wei Jian, Nan Li, Yinong Xie, Zhihua Li. Genetic etiology and pregnancy outcome of non-immune fetal edema syndrome: a Chinese cohort study[J]. Chinese Journal of Obstetric Emergency(Electronic Edition), 2022, 11(01): 38-45.

目的

探讨非免疫性胎儿水肿综合征(nonimmune hydrops fetalis，NIHF)非重型α地中海贫血胎儿的遗传学原因及妊娠结局。

方法

回顾性分析2014年1月至2020年7月在广州医科大学附属第三医院超声诊断为非免疫性胎儿水肿综合征病例116例，通过染色体核型分析/染色体微阵列分析(chromosome microarray analysis，CMA)/全外显子组测序(whole exome sequencing，WES)进行产前诊断，并分析其妊娠结局。

结果

103例单胎NIHF中45例(43.69%，45/103)有临床显著的产前诊断结果异常，其中30例染色体数目异常，9例有致病性/可能致病性拷贝数变异，6例有致病性/可疑致病/临床意义未明的变异。13例双胎及多胎之一NIHF中5例为非整倍体。81例单胎选择人工终止妊娠。19例单胎继续妊娠，除8例胎死宫内外，11例活产(6例早产，5例足月产)；其中4例(3例早产、1例足月产)接受了出生后手术(1例行室间隔修补术，1例行腹腔穿刺引流术，1例行回肠双腔造口术，1例行肠梗阻手术)，3例成功，1例术后夭折；6例未行手术者除1例生长发育迟缓，余生长发育正常。

结论

NIHF主要的遗传学病因是非整倍体异常、CNV异常及点突变，CMA对胎儿遗传学病因的检出率高于染色体核型分析，应被用于一线检查手段；WES是诊断NIHF的一个非常有价值的工具，可以发现罕见单基因遗传病。

关键词: 胎儿水肿, 核型分析, 微阵列分析, 外显子测序, 妊娠结局
Objective

To investigate the genetic causes and pregnancy outcome of nonimmune hydrops fetalis (NIHF).

Methods

We retrospectively recruited 116 cases of hydrops fetalis diagnosed by ultrasound in our hospital from January 2014 to July 2020. All the cases were undergone prenatal diagnosis by at least one of the following tests: 1) karyotyping, 2) chromosomal microarray analysis (CMA) or 3) whole exome sequencing (WES). The medical records of pregnancy outcome was retrieved and analyzed.

Results

Among 103 singleton pregnancies with NIHF, 45 cases (43.69%, 45/103) were reported to have clinically significant results including 30 cases with numerical disorders, 9 cases with pathogenic or likely pathogenic copy number variants (CNVs) and 6 cases with point mutations. Among 13 twin and multiple pregnancies with NIHF, 5 cases were diagnosed as aneuploidies. For the pregnancy outcome, 81singleton pregnancies were ended with termination of pregnancy. 19 singleton pregnancies chose to continue the pregnancy, except 8 cases died in utero. The remaining 11 cases were all live births, among which 6 cases were born premature and 5 cases were full-term. 4 cases (3 cases were premature, 1 case was in term deliveries) received post-birth surgical intervention, of which 3 cases were successful and 1 case died after operation. Among 6 cases without surgical intervention, 1 case had growth retardation and the other 5 cases manifested normal growth and development.

Conclusions

Numerical disorders, CNV disorders and point mutations are the main genetic causes of NIHF. The detection rate of CMA in NIHF is higher than chromosome karyotype analysis, so CMA should be used as a first-line method for genetic investigation of NIHF. WES is a valuable tool for the diagnosis of NIHF due to the ability to detect rare single-gene disorders.

Key words: Hydrops fetalis, Karyotyping, Chromosomal microarray analysis, Whole exome sequencing, Pregnancy outcome
表1 9例CMA检测到致病性/可能致病性拷贝数变异的胎儿特征及结局
胎儿例序 超声表现 CMA结果 片段长度 分类 结局
1 胎儿心脏增大、心包积液、腹水 arr[hg19]17q11.2(28，964，063-30，341，286)x3 1377 kb 致病 人工终止妊娠
2 心脏增大、心包积液、腹水、双肾积水、膀胱增大、壁厚，上尿道扩张，考虑后尿道瓣膜可能性大、羊水过少 arr[hg19]12p13.33p13.31(173，786-7，806，799)x3
arr[hg19]14q32.33(104，539，607-106，232，260)x1		 7633 kb
1693 kb		 致病
致病		 人工终止妊娠
3 胎儿心脏扩大、胎儿胸腹腔积液、胎儿肠管回声增强、胎儿阵发性心动过速 arr[hg19]1q42.3q44(236，509，301-249，224，684)x1
arr[hg19]13q31.3q34(93，051，804-115，107，733)x3		 12.7 Mb
22.0 Mb		 致病
致病		 人工终止妊娠
4 胎儿腹腔积液、右侧胸腔积液、胎儿皮下组织水肿、羊水过多 arr[hg19] 22q11.21(19，024，793-21，800，471)x1 2.77 Mb 致病 人工终止妊娠
5 腹腔积液、羊水过多、蛛网膜囊肿 arr[hg19] 17 p13.3 (1，154，011-2，091，257)×3 937 kb 致病 人工终止妊娠
6 胎儿全身皮肤水肿、心包腔积液、腹腔积液 arr[hg19] Xp22.31(6，455，151-8，135，568)x0 mat 1680 kb 异常母源性 人工终止妊娠
7 胎儿右侧膈疝、胸腔积液腹腔积液、羊水过多 arr[hg19]Y11.221q11.222(19588384-21028944)*0 1441 kb 不确定 人工终止妊娠
8 腹水、羊水过多、肠管回声增强、双侧侧脑室轻度增宽 arr[hg19] Xq28(152，916，789-153，029，189)x1 112 kb 不确定 人工终止妊娠
9 胸水、腹水、胎儿脑沟脑回消失、脑水肿 arr[hg19] 18q21.2(53，140，531-53，256，516)x1 116 kb 不确定 人工终止妊娠
表2 6例WES检测到的致病变异和临床意义未明变异的胎儿特征及结局
胎儿例序 疾病 变异来源 变异分类 合子状态 基因变异 参考序列 基因 超声表现 结局
10 胎儿运动不能序列综合征 父源(杂合)
母源(杂合)		 致病变异可疑致病 杂合
杂合		 C.790C>T
C．296G>T		 NM_005592.3
NM_005592.3		 MUSK
MUSK		 草莓头、左肺缺如、房间隔缺损、胃泡小、左足内翻、右手指形态异常、四肢姿势固定、皮下组织水肿、羊水过多 人工终止妊娠
11 Noonan综合征 父源(杂合) 可能致病 杂合 C.1510A>G(P.M504V) NM_002834 PTPN11 皮下水肿、双侧胸腔积液、少量腹水、羊水过多 人工终止妊娠
12 黏多糖贮积症Ⅶ型 父源(杂合)
母源(杂合)		 临床意义未明、可能致病 杂合
杂合		 C.512C>T
C．499C>T		 NM_000181.3
NM_000181.3		 GUSB
GUSB		 腹腔积液、胸腔积液、皮肤水肿 人工终止妊娠
13 淋巴管畸形6型
遗传性口形红细胞增多症1型		 父源(杂合)
母源(杂合)		 临床意义未明、致病变异 杂合
杂合		 C.2587T>C
C．3796+2T>G		 NM_001142864.4
NM_001142864.4		 PIEZO1
PIEZO1		 胸腔积液，皮肤水肿 人工终止妊娠
14 糖原贮积症Ⅳ型 父源(杂合)
母源(杂合)		 临床意义未明、临床意义未明 杂合
杂合		 C.1750G>C
C．1619-6A>G		 NM_000158.4
NM_000158.4		 GBE1
GBE1		 腹腔积液、胸腔积液、皮肤水肿 人工终止妊娠
15 先天再生障碍性贫血12型 新发突变 致病性 杂合 C.34A>T NM_002948.4 RPL15 腹腔积液、皮肤水肿、心脏增大，心肌肥厚、主动脉弓部狭窄，左肺发育偏小 引产
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