胎儿尿路扩张的遗传学相关性与妊娠结局分析

Analysis of genetic association and pregnancy outcomes of fetal urinary tract dilation

摘要

目的 分析胎儿尿路扩张(UTD)与染色体异常的遗传相关性及胎儿妊娠结局,探讨胎儿尿路扩张的临床咨询及预后。方法 选取2019年1月至2022年12月在安徽省立医院产检超声提示胎儿UTD的903份病例作为研究对象,对已行介入性产前诊断的239例UTD胎儿的遗传学检测结果进行分析并随访其妊娠结局及胎儿预后情况。根据是否合并其它系统超声软指标异常分为孤立UTD组93例,非孤立UTD组146例。结果 903份UTD胎儿中,239例已行介入性产前诊断。单一染色体核型阳性检出7例:47,XX,+8[4]/46,XX[6q]1例、46,XY,inv(9)(p12q13)2例、45,XY,der(13;14)(q10;q10)1例、45,XX,der(13;15)(q10;q10)1例、46,XX,-22,+mar1例、46,XX,21pstk+1例。单一基因组拷贝数变异测序(CNV-seq)阳性检出9例:15q13.2q13.3微缺失1例、8p23.1微重复1例、Xq11.1q28微重复合并Xp11.23p11.1微重复1例、15q11.2微缺失1例、15q11.2q11.2微缺失合并16p11.2p11.2微重复1例,16p13.1p12.3微缺失1例,15q11.2q11.2微缺失2例,5q23.2q23.2微重复1例。染色体核型及CNV-seq两者均阳性检出21三体综合征1例。其中,孤立组染色体核型检出异常3例,非孤立组染色体核型检出异常7例;孤立组CNV-seq检出致病/疑似致病变异2例,非孤立组CNV-seq检出致病/疑似致病8例,两组染色体异常率差异无统计学意义(χ²=1.015,P>0.05)。预后情况:239例行介入性产前诊断胎儿中,失访13人,随访成功226例(随访成功率94.56%)。遗传咨询后知情选择终止妊娠14例(孤立UTD组4例,非孤立UTD组10例),1例非孤立UTD组自然流产(脐带扭转),活产211例(孤立UTD组82例、非孤立UTD组129例)。其中,孤立UTD组24例、非孤立UTD组15例在胎儿出生后复查仍有尿路扩张,后续定期复查,随访时生长发育均未见明显异常。孤立UTD组胎儿出生后手术7人,非孤立UTD组胎儿出生后手术1人,余活产儿生长发育均未见明显异常。结论 孤立尿路扩张组胎儿与非孤立尿路扩张组的染色体异常检出率无显著差异,提示无论尿路扩张是否合并其他超声异常,均应建议行介入性产前诊断以排除遗传学病因。染色体核型分析联合CNV-seq可显著提高尿路扩张胎儿的遗传学病因检出率。妊娠结局随访显示,尿路扩张胎儿总体预后良好,手术干预后尿路扩张疾病得以改善。

Abstract

Objective To analyze the genetic association between fetal urinary tract dilation (UTD) and chromosomal abnormalities,as well as the pregnancy outcomes,and to explore the clinical counseling and prognosis of fetal UTD. Methods A total of 903 fetuses with UTD detected by prenatal ultrasonography who underwent prenatal examination at Anhui Provincial Hospital from January 2019 to December 2022 were selected as the study subjects.Genetic testing results of 239 UTD fetuses who had undergone invasive prenatal diagnosis were analyzed,and their pregnancy outcomes and fetal prognosis were followed up.According to whether other ultrasonographic soft markers were present,the fetuses were divided into an isolated UTD group (n=93) and a non-isolated UTD group (n=146). Results Among the 903 UTD fetuses,239 cases had undergone invasive prenatal diagnosis.Karyotyping alone detected 7 positive cases:47,XX,+8[4]/46,XX[6q] in 1 case,46,XY,inv(9)(p12q13) in 2 cases,45,XY,der(13;14)(q10;q10) in 1 case,45,XX,der(13;15)(q10;q10) in 1 case,46,XX,-22,+mar in 1 case,and 46,XX,21pstk+ in 1 case.CNV-seq alone identified 9 positive cases:15q13.2q13.3 microdeletion in 1 case,8p23.1 microduplication in 1 case,Xq11.1q28 microduplication combined with Xp11.23p11.1 microduplication in 1 case,15q11.2 microdeletion in 1 case,15q11.2q11.2 microdeletion combined with 16p11.2p11.2 microduplication in 1 case,16p13.1p12.3 microdeletion in 1 case,15q11.2q11.2 microdeletion in 2 cases,and 5q23.2q23.2 microduplication in 1 case.Both karyotyping and CNV-seq detected trisomy 21 in 1 case.Among these,three chromosomal abnormalities were detected in the isolated UTD group,while seven chromosomal abnormalities were detected in the non-isolated UTD group.Two pathogenic/likely pathogenic CNV-seq variants were detected in the isolated UTD group,whereas eight pathogenic/likely pathogenic variants were detected in the non-isolated UTD group.There was no statistically significant difference in chromosomal abnormality rates between the two groups (χ ²=1.015,P>0.05).Regarding prognosis:among the 239 fetuses who underwent invasive prenatal diagnosis,13 were lost to follow-up,and 226 cases were successfully followed up (follow-up success rate 94.56%).After genetic counseling,14 cases chose to terminate pregnancy with informed consent (4 in the isolated UTD group and 10 in the non-isolated UTD group),and 1 case in the non-isolated UTD group experienced spontaneous abortion (umbilical cord torsion).There were 211 live births (82 in the isolated UTD group and 129 in the non-isolated UTD group).Among them,24 cases in the isolated UTD group and 15 cases in the non-isolated UTD group still had urinary tract dilation upon postnatal re-examination,with subsequent regular follow-up,and no obvious abnormalities in growth and development were observed at follow-up.Seven cases in the isolated UTD group and 1 case in the non-isolated UTD group underwent postnatal surgery,while the remaining live-born infants showed no obvious abnormalities in growth and development. Conclusion There was no significant difference in the detection rate of chromosomal abnormalities between the isolated UTD group and the non-isolated UTD group,suggesting that invasive prenatal diagnosis should be recommended regardless of whether UTD is accompanied by other ultrasonographic abnormalities in order to exclude genetic etiologies.Combined karyotype analysis and CNV-seq can significantly improve the detection rate of genetic abnormalities in fetuses with UTD.Follow-up of pregnancy outcomes indicated that the overall prognosis of fetuses with UTD was favorable,and postnatal surgical intervention effectively improved urinary tract dilation.

关键词

胎儿 / 尿路扩张 / 产前诊断 / 染色体异常 / 核型分析 / CNV-seq / 妊娠结局

Key words

fetus / urinary tract dilation / prenatal diagnosis / chromosomal abnormality / karyotype analysis / CNV-seq / pregnancy outcome

参考文献

[1] Liu W, Shi X, Li Y, et al. The evaluation of genetic diagnosis on high-risk fetal CAKUT[J]. Front Genet, 2022,13: 869525.

[2] Koenigbauer J T, Laura Fangmann, Charlotte Reinhardt, et al. Spectrum of congenital anomalies of the kidney and urinary tract (CAKUT) including renal parenchymal malformations during fetal life and the implementation of prenatal exome sequencing(WES)[J]. Arch Gynecol Obstet, 2024,309(6): 2613-2622.

[3] Zivotic I, Kolic I, Cvetkovic M, et al. Copy number variation analysis identifies MIR9-3 and MIR1299 as novel miRNA candidate genes for CAKUT[J]. Pediatr Nephrol, 2024,39(9): 2655-2665.

[4] 唐丽君. 胎儿先天性肾脏及泌尿道异常的产前精准诊断初探[D]. 南方医科大学, 2023.

[5] 黎冬梅, 陈红, 镡颖, 等. 先天性泌尿系统畸形胎儿的染色体核型及拷贝数变异产前诊断结果分析[J]. 实用妇产科杂志, 2023,39(4): 297-301.

[6] 马海霞, 冯丽云, 郭苑青, 等. 染色体核型分析联合CNV-Seq检测在高龄孕妇产前诊断中的应用[J]. 检验医学与临床, 2024,21(4): 507-510.

[7] 张素华, 徐月新, 傅丹. 羊水细胞染色体核型分析联合基因组拷贝数变异测序技术在产前诊断中的应用[J]. 国际检验医学杂志, 2021,42(10): 1166-1170, 1175.

[8] Riggs E R, Andersen E F, Cherry A M, et al. Technical standards for the interpretation and reporting of constitutional Copy-number variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)[J]. Genet Med, 2020,22(2): 245-257.

[9] Pavlovic N, Kriznac M, Kumric M, et al. Mitochondrial dysfunction:the silent catalyst of kidney disease progression[J]. Cells, 2025,14(11): 794.

[10] Lina W, Helge M, Imke H, et al. Diagnostic yield and benefits of whole exome sequencing in UTD patients diagnosed in the first thousand days of life[J]. Kidney Int Rep, 2023,8(11): 2439-2457.

[11] Baldwin I, Shafer R L, Hossain W A, et al. Genomic,clinical,and behavioral characterization of 15q11.2 BP1-BP2 deletion (burnside-butler) syndrome in five families[J]. Int J Mol Sci, 2021;22(4): 1660.

[12] Leskur M, Leskur D, Marijan S, et al. Congenital anomalies of the kidney and urinary tract in down syndrome:prevalence,phenotypes,genetics and clinical management[J]. Genes, 2025,16(3): 245.

[13] Mahmoud A H, Talaat I M, Tlili A, et al. Congenital anomalies of the kidney and urinary tract[J]. Frontiers in Medicine, 2024(11): 1384676.

[14] Rafi S K, Butler M G. The 15q11.2 BP1-BP2 microdeletion (burnside-butler) syndrome:in silico analyses of the four coding genes reveal functional associations with neurodevelopmental phenotypes[J]. Int J Mol Sci, 2020,21(9): 3296.

[15] Palumbi R, Ponzi E, Micella S. Clinical phenotype of the 16p.13.11 microdeletion:a case report with a mini review of the literature[J]. Front Genet, 2024,16(15): 1429185.

[16] Hicks M A, Ebrahim S, Gonik B. Prenatal lethal diagnosis of 8p23.1 duplication syndrome associated with omphalocele and encephalocele[J]. Case Rep Genet, 2023,25: 5958223.

[17] Leffler M, Christie L, Hackett A. Further delineation of dosage-sensitive K/L mediated Xq28 duplication syndrome includes incomplete penetrance[J]. Clin Genet, 2023,103(6): 681-687.

[18] 钟丽娟, 陈艳, 钟容, 等. CNV-seq结合染色体核型分析技术在产前诊断胎儿染色体异常中的价值观察[J]. 中国妇幼健康研究, 2024,35(8): 69-75.

[19] 吴秋华, 石凤蕊, 王瑞, 等. CNV-seq应用于产前诊断及流产物检测意外发现DMD基因变异临床分析[J]. 中国妇幼健康研究, 2024,35(6): 75-82.

基金资助

安徽省高等学校科学研究项目(2024AH052040)