一例嵌合型Beckwith-Wiedemann综合征的分子诊断与分析

doi:10.12280/gjfckx.20221010

摘要/Abstract

摘要：

报告1例产前超声提示左肾囊肿、羊水偏多的孕妇行产前诊断，经咨询后要求对胎儿进行遗传学检测，以明确临床诊断。采用染色体微阵列分析（chromosomal microarray analysis，CMA）和全外显子组测序（whole exome sequencing，WES）技术对胎儿羊水细胞DNA进行分析。CMA检测结果显示胎儿染色体11p15.5p15.1区域存在片段大小约为18.6 Mb的嵌合型单亲二体（uniparental disomy，UPD）；WES检测范围内未发现明确的致病性基因变异。为明确胎儿嵌合型UPD的亲本来源，进一步采用甲基化特异性多重连接探针扩增技术（methylation-specific multiplex ligation-dependent probe amplification，MS-MLPA）检测胎儿印迹区域甲基化异常情况，结果显示胎儿印迹中心域1（imprinting center region 1，ICR1）区甲基化水平升高，ICR2区甲基化水平降低，因此可判定胎儿11p15.5p15.1区域为父源性嵌合UPD，从而确诊胎儿为Beckwith-Wiedemann综合征（Beckwith-Wiedemann Syndrome，BWS）。BWS产前超声常为非特异性表现，极易造成漏诊和误诊，因此选择正确且有针对性的分子诊断技术异常重要，避免缺陷患儿的出生。

关键词: Beckwith-Wiedemann综合征, 单亲二体性, 染色体, 微阵列分析, 甲基化, 产前诊断

Abstract:

A pregnant woman with left renal cyst and excessive amniotic fluid diagnosed by prenatal ultrasound was reported. After consultation, genetic testing of the fetus was requested to clarify the clinical diagnosis. Subsequently, chromosomal microarray analysis (CMA) and whole exome sequencing (WES) were used to analyze the DNA of fetal amniotic fluid cells. CMA results showed that there was a chimeric uniparental disomy (UPD) with a fragment size of about 18.6 Mb in the 11p15.5p15.1 region of the fetal chromosome. Simultaneously, no clear pathogenic gene mutations were found within the WES detection range. To clarify the parental origin of fetal chimeric UPD, the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) for Beckwith-Wiedemann syndrome (BWS) was further used to detect abnormal methylation in the fetal imprinted region. The MS-MLPA results demonstrated that the methylation level in the imprinting center region 1 (ICR1) region of the fetus increased, while the methylation level in the ICR2 region decreased. Therefore, it can be determined that the fetal 11p15.5p15.1 region is a paternal chimeric UPD, thereby confirming that the fetus is BWS. Prenatal ultrasound of BWS is often a non-specific manifestation, which easily leads to missed diagnosis and misdiagnosis. Therefore, it is extremely important to carry out correct and targeted molecular diagnostic techniques to avoid the birth of defective children.

Key words: Beckwith-Wiedemann syndrome, Uniparental disomy, Chromosomes, Microarray analysis, Methylation, Prenatal diagnosis

郭静, 朱重阳, 李鹏云, 王涵铎, 刘灵. 一例嵌合型Beckwith-Wiedemann综合征的分子诊断与分析[J]. 国际妇产科学杂志, 2023, 50(4): 442-445.

GUO Jing, ZHU Chong-yang, LI Peng-yun, WANG Han-duo, LIU Ling. Molecular Diagnosis and Analysis of A Fetus with Chimeric Beckwith-Wiedemann Syndrome[J]. Journal of International Obstetrics and Gynecology, 2023, 50(4): 442-445.

图/表 2

图1 胎儿染色体CMA结果注：A为CMA芯片Copy Number State、log2 Ratio、Allele Difference、BAF（B allele frequency）图，红框所示区域为11 p15.5p15.1区域，结合该区域上方的Copy Number State为2，Allele Difference和BAF散点图分布为4条线，判断此部分发生节段性嵌合UPD；B为CMA芯片全基因组视图（whole genome view，WGV），红框表示11号染色体的拷贝数情况和基因型情况。

图2 胎儿的MS-MLPA结果注：上方柱状图反映拷贝数变化，下方柱状图反映ICR1（H19/IGF2：IG-DMR）和ICR2（KCNQ1OT1：TSS-DMR）区域的甲基化变化。

参考文献 11

[1]	Brioude F, Kalish JM, Mussa A, et al. Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement[J]. Nat Rev Endocrinol, 2018, 14(4):229-249. doi: 10.1038/nrendo.2017.166. doi: 10.1038/nrendo.2017.166 pmid: 29377879
[2]	Wiedemann HR. Familial malformation complex with umbilical hernia and macroglossia--a "new syndrome"?[J]. J Genet Hum, 1964, 13:223-232.
[3]	Radley JA, Connolly M, Sabir A, et al. Isolated- and Beckwith-Wiedemann syndrome related-lateralised overgrowth (hemihypertrophy): Clinical and molecular correlations in 94 individuals[J]. Clin Genet, 2021, 100(3):292-297. doi: 10.1111/cge.13997. doi: 10.1111/cge.13997
[4]	Eggermann T, Maher ER, Kratz CP, et al. Molecular Basis of Beckwith-Wiedemann Syndrome Spectrum with Associated Tumors and Consequences for Clinical Practice[J]. Cancers (Basel), 2022, 14(13):3083. doi: 10.3390/cancers14133083. doi: 10.3390/cancers14133083
[5]	Aygun D, Bjornsson HT. Clinical epigenetics: a primer for the practitioner[J]. Dev Med Child Neurol, 2020, 62(2):192-200. doi: 10.1111/dmcn.14398. doi: 10.1111/dmcn.14398 pmid: 31749156
[6]	Fontana L, Tabano S, Maitz S, et al. Clinical and Molecular Diagnosis of Beckwith-Wiedemann Syndrome with Single- or Multi-Locus Imprinting Disturbance[J]. Int J Mol Sci, 2021, 22(7):3445. doi: 10.3390/ijms22073445. doi: 10.3390/ijms22073445
[7]	Wesseler K, Kraft F, Eggermann T. Molecular and Clinical Opposite Findings in 11p15.5 Associated Imprinting Disorders: Characterization of Basic Mechanisms to Improve Clinical Management[J]. Int J Mol Sci, 2019, 20(17):4219. doi: 10.3390/ijms20174219. doi: 10.3390/ijms20174219
[8]	Ma GC, Chen TH, Wu WJ, et al. Proposal for Practical Approach in Prenatal Diagnosis of Beckwith-Wiedemann Syndrome and Review of the Literature[J]. Diagnostics (Basel), 2022, 12(7):1709. doi: 10.3390/diagnostics12071709. doi: 10.3390/diagnostics12071709
[9]	de Vasconcelos Gaspar A, Branco M, Galhano E, et al. Ultrasound and molecular prenatal diagnosis of Beckwith-Wiedemann syndrome: Two case reports[J]. Radiol Case Rep, 2022, 17(12):4914-4919. doi: 10.1016/j.radcr.2022.09.066. doi: 10.1016/j.radcr.2022.09.066
[10]	Shin CH, Lim C, Kim HY, et al. Prospective study of epigenetic alterations responsible for isolated hemihyperplasia/hemihypoplasia and their association with leg length discrepancy[J]. Orphanet J Rare Dis, 2021, 16(1):418. doi: 10.1186/s13023-021-02042-6. doi: 10.1186/s13023-021-02042-6 pmid: 34627330
[11]	Jessica AR, Melissa C, Ataf S, et al. Isolated- and Beckwith-Wiedemann syndrome related-lateralised overgrowth (hemihypertrophy): Clinical and molecular correlations in 94 individuals[J]. Clin Genet, 2021, 100(3):292-297. doi: 10.1111/cge.13997. doi: 10.1111/cge.13997 pmid: 33993487

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