Fetal cystic hygroma (CH) is associated with poor prognosis and chromosomal anomalies. Recent studies have suggested that the genetic background of affected fetuses is essential for predicting pregnancy outcomes. However, the detection performance of different genetic approaches for the etiological diagnosis of fetal CH remains unclear. In this study, we aimed to compare the diagnostic efficiency of karyotyping and chromosomal microarray analysis (CMA) in a local fetal CH cohort, and tried to propose an optimized testing strategy that may help improve the cost-effectiveness of disease management. We reviewed all pregnancies that underwent invasive prenatal diagnosis between January 2017 and September 2021 at one of the largest prenatal diagnostic centers in Southeast China. We collected cases identified by the presence of fetal CH. Prenatal phenotypes and laboratory records of these patients were audited, collated, and analyzed. The detection rates of karyotyping and CMA were compared, and the concordance rate of these two methods was calculated. A total of 157 fetal CH cases were screened from 6,059 patients who underwent prenatal diagnosis. Diagnostic genetic variants were identified in 44.6% (70/157) of the cases. Karyotyping, CMA, and whole-exome sequencing (WES) identified pathogenic genetic variants in 63, 68, and 1 case, respectively. The Cohen’s κ coefficient between karyotyping and CMA was 0.96, with a concordance of 98.0%. Of the 18 cases in which cryptic copy number variants <5 Mb were detected by CMA, 17 were interpreted as variants of uncertain significance, and the remaining cases were interpreted as pathogenic. Trio exome sequencing revealed a pathogenic homozygous splice site mutation in the PIGN gene in a case undiagnosed by CMA and karyotyping. Our study demonstrated that chromosomal aneuploidy abnormalities are the main genetic cause of fetal CH. Based on this, we recommend karyotyping combined with rapid aneuploidy detection as a first-tier approach for the genetic diagnosis of fetal CH. WES and CMA could improve the diagnostic yield when routine genetic tests fail to determine the cause of fetal CH.

Fetal cystic hygroma (CH), also known as cystic lymphangioma, is a relatively rare abnormality in prenatal ultrasound screening [Scholl et al., 2012]. Similar to increased nuchal translucency (NT), CH is usually found in the fetal neck at NT measurement. However, anatomical and pregnancy outcome differences exist between CH and NT [Scholl et al., 2012]. Previous studies revealed that common aneuploidies may play an important role in the etiology of CH; thus, in most relevant studies, CH was regarded as a soft marker for fetal aneuploidies, and only karyotyping has been conducted to explore the cause of the disease [Ganapathy et al., 2004; Malone et al., 2005; Kharrat et al., 2006; Ozcan et al., 2019; Levy et al., 2021; Malone et al., 2021]. However, at the same time, some scholars considered fetal CH as a structural malformation [Shaffer et al., 2012; Fiorentino et al., 2013] and advocated the use of chromosomal microarray analysis (CMA) either alone or in combination with karyotyping to clarify the etiology of CH. Although CH was classified as a soft marker in a recent guideline, there was no mention of which method should be recommended as priority testing for patients [Rose et al., 2020]. To the best of our knowledge, studies comparing CMA with karyotyping for the diagnosis of CH are rare. In 2020, the American College of Medical Genetics and Genomics (ACMG) further recommended that whole-exome sequencing (WES) should be used as a second-tier approach in cases where karyotyping and chromosomal microarray fail to determine the underlying cause of a structural anomaly [Monaghan et al., 2020]. We retrospectively collected and reviewed a series of cases of fetal CH in one of the largest prenatal diagnosis centers in Southeastern China. We analyzed and compared the laboratory findings in our cohort and propose a strategy for the genetic diagnosis of fetal CH in a clinical setting.

Study Participants

This retrospective cohort study was based on a review of the medical records of pregnant women who underwent invasive prenatal testing for CH at the Women and Children’s Hospital, School of Medicine, Xiamen University (Xiamen, China), between January 2017 and September 2021. Clinical data, including gestational age at CH detection, prenatal sonographic findings, genetic testing results, and pregnancy outcomes, were reviewed.

Genetic Testing

Karyotyping was performed in-house, according to standard methods [Jiang et al., 2021]. Chromosomal microarray analysis was conducted by Be Creative Lab (Beijing) Co., Ltd., using the CytoScan® 750K Array Suite kit (Cat. No. 901859; Affymetrix, Inc., Thermo Fisher Scientific, Inc.), according to the manufacturer’s protocol. Based on the laboratory policy at the time, fragment deletions <100 kb or duplications <200 kb were not reported. Reported outcomes include copy number variants (CNVs) interpreted as pathogenic or likely pathogenic, variants of uncertain significance (VOUS), absence of heterozygosity >10 Mb, and a proportion of mosaic abnormal cells >30%. All abnormal CNVs were audited in-house by clinical geneticists and genetic counselors, according to the current ACMG guidelines [Riggs et al., 2020]. Exome sequencing was performed by BGI Genomics (BGI-Shenzhen, China) using their standard procedures. Candidate variants were interpreted according to ACMG and the Association for Medical Pathology criteria [Richards et al., 2015]. The reported turnaround times for karyotyping, CMA, and WES in our hospital are 15, 10, and 15 working days, respectively.

Statistical Methods

Categorical variables were summarized as percentages and proportions. Cohen’s κ coefficient was used to measure the concordance of results between karyotyping and CMA.

Cohort Characteristics

Between January 2017 and September 2021, 6,059 pregnant women underwent invasive prenatal testing at our hospital for different referral indications. Of these, 157 (2.59%) had fetal CH identified by ultrasound screening according to the definition of the First and Second Trimester Evaluation of Risk (FASTER) trial Research Consortium (An enlarged hypoechoic space at the back of the fetal neck, extending along the length of the fetal back with clear visible septations irrespective of NT thickness) [Malone et al., 2005], and were included in the study cohort (online suppl. Table S1; see www.karger.com/doi/10.1159/000528600). Of these 157 CH cases, 142 were detected in the first trimester and the remaining 15 were identified in the second trimester. The mean gestational age at fetal CH detection was 13 weeks (range, 11–25 weeks). Most patients underwent both CMA and karyotyping, but 4 patients declined karyotype testing and underwent CMA only. Trio exome sequencing was performed for families with recurrent fetal abnormalities. The sources of fetal DNA were chorionic villus sampling (51%, 80/157), amniocentesis (46%, 72/157), and umbilical cord blood (3%, 5/157).

Comprehensive Genetics Profile of the Fetal CH Cohort

As presented in Figure 1, laboratory findings were obtained for all CMA tests, but one chorionic villus sample (CVS) was not detected by karyotyping because of cell culture failure. The detection success rates for CMA and karyotyping were 100% and 99.3% (152/153), respectively. Sixty-three pathogenic chromosomal aberrations were detected by karyotyping; all but one (a case of low-level mosaicism) were confirmed by CMA. Six additional meaningful results in cases with normal karyotypes or without karyotyping were detected by CMA. Cohen’s κ coefficient between the CMA and karyotyping was 0.96, with a concordance of 98.0%, indicating nearly perfect agreement. In one case that was negative by CMA and karyotyping, trio exome sequencing revealed a pathogenic homozygous splice site mutation in the PIGN gene. The overall detection rate in our cohort was 44.6% (70/157).

Fig. 1.

Overall results of karyotyping and chromosomal microarray analysis in 157 prenatal diagnosis cases with fetal cystic hygroma. CMA, chromosomal microarray analysis; CNVs, copy number variants; mar, marker chromosome; der, derivative chromosome; inv, chromosome inversion; dup, duplication; del, deletion; com, complex rearrangement involving deletion and duplication.

Fig. 1.

Overall results of karyotyping and chromosomal microarray analysis in 157 prenatal diagnosis cases with fetal cystic hygroma. CMA, chromosomal microarray analysis; CNVs, copy number variants; mar, marker chromosome; der, derivative chromosome; inv, chromosome inversion; dup, duplication; del, deletion; com, complex rearrangement involving deletion and duplication.

Close modal

Numerical Chromosomal Abnormalities and Structural Chromosomal Rearrangements

One case of supernumerary marker chromosomes (46,X,+mar) and 54 cases of common aneuploidies were detected using karyotyping. These variabilities were verified using CMA, which confirmed that the marker chromosomes did not contain any disease genes, and we, therefore, classified the case as aneuploidy (Turner syndrome). In 4 cases, in which karyotyping was not performed or cell culture failed, CMA also detected aneuploidies. Adding 1 case of Patau syndrome with maternally inherited robertsonian translocation der(13;15), karyotyping combined with CMA identified 60 cases involving complete duplication or deletion of chromosomes 21, 18, 13, or X, accounting for 38.2% (60/157) of all CH cases. Among these 60 cases, there were 25 cases of monosomy X (41.7%), 17 cases of trisomy 21 (28.3%), 14 cases of trisomy 18 (23.3%), 3 cases of trisomy 13, and 1 case of 47,XXY. Karyotyping detected structural chromosome rearrangements in 7 cases (Table 1) in addition to the aforementioned robertsonian translocation, including 3 cases each of terminal deletions and derivative chromosomes. All of these chromosomal abnormalities were confirmed using CMA.

Table 1.

Fetal cystic hygroma with unbalanced chromosome rearrangement detected by karyotyping and CMA

 Fetal cystic hygroma with unbalanced chromosome rearrangement detected by karyotyping and CMA
 Fetal cystic hygroma with unbalanced chromosome rearrangement detected by karyotyping and CMA

Mosaicism

One case (Table 2, case 123) of sex chromosome mosaicism was detected by karyotyping but missed by CMA. Subsequent interphase fluorescence in situ hybridization (FISH) testing of uncultured amniotic fluid cells indicated low-level mosaicism of 47,XXY and 45,X cells. In 6 other cases, CMA also detected mosaicism in cultured cells; 4 showed non-mosaic aneuploidies and the other 2 had normal karyotypes. One case (Table 2, case 63) with suspected mosaic ring chromosomes by CMA, but a normal karyotype, was classified as pathogenic according to the proportion and size of abnormal chromosomal segments.

Table 2.

Fetal cystic hygroma with mosaic abnormalities detected by karyotyping or CMA

 Fetal cystic hygroma with mosaic abnormalities detected by karyotyping or CMA
 Fetal cystic hygroma with mosaic abnormalities detected by karyotyping or CMA

Submicroscopic CNVs and Single-Nucleotide Variants

As shown in Table 3, CMA identified 18 cases with CNVs smaller than 5 Mb, and 8 cases were combined with numerical or structural chromosomal abnormalities. The remaining 10 cases had normal karyotypes; one had a 1.4-Mb microdeletion at 17q12, which was interpreted as pathogenic, and the other 17 CNVs were classified as VOUS. In a fetus with multiple structural abnormalities (Table 3, case 81), a homozygous splice site mutation in the PIGN gene (NM_176787.4: exon8:c.963G>A, p.Gln321Gln) was detected by WES and verified by Sanger sequencing.

Table 3.

Fetal cystic hygroma with cryptic CNVs <5 Mb detected by CMA and sequence variant detected by WES

 Fetal cystic hygroma with cryptic CNVs <5 Mb detected by CMA and sequence variant detected by WES
 Fetal cystic hygroma with cryptic CNVs <5 Mb detected by CMA and sequence variant detected by WES

Clinical Recommendations for Prenatal Genetic Diagnosis of Fetal CH

Based on the data obtained in this study, we propose a prenatal genetic diagnostic workflow for fetal CH (Fig. 2). We recommend rapid aneuploidy detection (RAD) by quantitative fluorescent polymerase chain reaction (QF-PCR) [Association for Clinical Cytogenetics and Clinical Molecular Genetics Society, 2012] or Prenatal BACs-on-Beads assay (PNBobsTM) [Jiang et al., 2021] instead of CMA in combination with karyotyping as the first-tier approach for rapid exclusion or confirmation of the most frequent genetic etiologies of fetal CH following a detailed ultrasound examination. In patients with negative RAD and normal karyotype results, CMA in conjunction with WES should be discussed, particularly when an additional fetal structural abnormality or recurrent fetal CH is present.

Fig. 2.

Flowchart for the prenatal genetic diagnosis and follow-up of patients with fetal cystic hygroma. CH, cystic hygroma; RAD, rapid aneuploidy detection; CMA, chromosomal microarray analysis; WES, whole-exome sequencing; Neg, negative result; Pos, positive result; GC, genetic counseling.

Fig. 2.

Flowchart for the prenatal genetic diagnosis and follow-up of patients with fetal cystic hygroma. CH, cystic hygroma; RAD, rapid aneuploidy detection; CMA, chromosomal microarray analysis; WES, whole-exome sequencing; Neg, negative result; Pos, positive result; GC, genetic counseling.

Close modal

Despite the similarities in the location and clinical manifestations of CH and NT, previous studies have shown that fetal CH is rare and strongly associated with poor pregnancy outcomes, and common chromosomal aneuploidies may contribute as the major genetic cause [Malone et al., 2005; Graesslin et al., 2007; Shaffer et al., 2012; Mack et al., 2017]. To date, there is no consensus on the nature of fetal CH [Malone et al., 2005; Kharrat et al., 2006]. In a study by Shaffer et al. [2012], fetal CH was categorized as a structural anomaly in the abnormal body fluid category, and several cases were diagnosed using CMA only. In another study conducted by Sparks et al. [2020], both increased NT and CH were classified as nonimmune hydrops fetalis, and diagnostic results were obtained by WES in some affected fetuses. As can be seen, heterogeneity is present in the etiology of fetal CH, and accurate, rapid identification of the genetic background of the affected fetus is essential for assessing prognosis and guiding the management of the pregnancy. In this study, we reviewed a Chinese cohort with fetal CH, mostly tested by both karyotyping and CMA, primarily to assess the diagnostic performance of these two assays for fetal CH and provide a basis for the rational application of genetic detection approaches in future clinical settings.

Common Aneuploidies and Structural Chromosomal Rearrangements Detected in Fetuses with CH

In the present study, 37.6% (59/157) of cases involved whole autosomal chromosome deletions or duplications, which was lower than the incidence reported by Malone et al. [2021] (47.7%; 63/132), Yakistiran et al. [2020] (50.6%; 43/85), and Kharrat et al. [2006] (60%; 25/42), but close to the 35.8% (10/28) reported by Ozcan et al. [2019]. These data indicate that autosomal chromosomal aneuploidies, including nondisjunctions and translocations, are the main genetic causes of fetal CH. Although an association between increased NT and Klinefelter syndrome has been previously reported [Sebire et al., 1998; van Huizen et al., 2005], an association between fetal CH and 47,XXY has not been stated. Here, for the first time, we report the presence of CH in a fetus with a 47,XXY karyotype. However, the phenotype-genotype association remains unclear.

Three cases of isolated chromosomal terminal deletions were identified by karyotyping and CMA in our cohort (Table 1, cases 14, 85, and 118). Previously, CH has been reported in fetuses prenatally diagnosed with Wolf-Hirschhorn syndrome [Xing et al., 2018; Zhen et al., 2018]. Increased NT or CH has also been reported in fetuses diagnosed with a 10q26 deletion [Grande et al., 2015]. Thus, our findings support an association between CH and the two CNVs. One case with a deletion of 13q33q34 was detected in our cohort. To date, this type of deletion has not been reported in fetuses with CH.

Mosaicism Detected in Fetuses with CH

Mosaicism can be prenatally diagnosed using conventional cytogenetics or molecular testing. Seven cases in our cohort showed mosaicism by karyotyping or CMA, but the results were discrepant. Three CVSs showed mosaic aneuploidy by CMA but non-mosaic aneuploidy by karyotyping (Table 2, cases 37, 62, and 104), while another 3 cases showed mosaic chromosomal segments by CMA but a single cell line in cultured cells (Table 2, cases 26, 63, and 151). The discrepancy between karyotyping and molecular testing during prenatal diagnosis is not uncommon, especially when the specimen is a CVS [Waters et al., 2006; Lau et al., 2009; Hamilton and Waters, 2012]. The differential growth rates of cell lines and selective cell loss are considered the major causes of such discrepancies [Lau et al., 2009]. In such cases, molecular detection methods are believed to provide additional information on the existence of different cell lines, as DNA is derived from uncultured cells [Hamilton and Waters, 2012]. The discrepancies in our cohort suggest that aneuploid cell lines may have a growth advantage over diploid cell lines, and that cells with marker chromosomes or ring chromosomes are easily lost in culture. One CVS had a negative CMA result (Table 2, case 123), but karyotyping showed a low-level mosaic gain of the X chromosome, and 3 cell lines were observed by FISH in uncultured amniotic fluid cells. The level of the abnormal cell lines was below the threshold for CMA detection. Low et al. [2017] reported a case of a male fetus presenting with CH and edema in the first trimester – QF-PCR and FISH of a CVS suggested XXY/XX mosaicism with a predominance of the 47,XXY cell line, and subsequent testing of amniotic fluid suggested that the proportions of abnormal and normal cells were comparable. A detailed fetal anomaly scan in the second trimester showed that the CH and body edema had completely regressed, and the baby was delivered vaginally in good condition. Based on these findings, the authors suggested that the association between CH and the 47,XXY karyotype remained unclear. Therefore, the low level 47,XXY mosaicism observed in our study may not explain the occurrence of fetal CH. A study conducted in the UK suggested that any evidence of mosaicism detected either by molecular testing and/or cultured cell karyotyping should be verified by ultrasound findings and/or interphase FISH testing of uncultured amniotic fluid cells [Hamilton and Waters, 2012]. However, in the present study, 6 of 7 mosaic cases refused further genetic testing to verify mosaicism, and 5 of 7 opted for termination of pregnancy due to fetal edema.

Submicroscopic CNVs Detected in Fetuses with CH

To date, data comparing the detection performance of CMA and karyotyping for fetal CH are rare. In an earlier study conducted by Shaffer et al. [2012], CMA identified pathogenic CNVs in 7.3% (22/302) of fetal CH cases, of which 12 were smaller than 10 Mb. Although the location and size of these CNVs were not presented, the authors assumed that these CNVs were unlikely to be identified by karyotyping. In contrast, in our study, two cases with deletions of chromosome ends smaller than 10 Mb were detected using both CMA and karyotyping. In addition, CMA identified microduplications/microdeletions smaller than 5 Mb in 18 cases. Among them, 10 had normal karyotypes, and only a 1.4-Mb microdeletion at chromosome 17q12 (Table 3, case 59) was interpreted as pathogenic. The most common clinical characteristics of fetuses with 17q12 microdeletion syndrome are renal anomalies, including hyperechogenic kidneys and multicystic renal dysplasia [Wan et al., 2019; Zhou et al., 2021]. In our case, fetal ultrasound identified a polycystic kidney at 16 weeks of gestation, whereas CH was identified at 12 weeks of gestation. To our knowledge, no previous reports have linked fetal CH to the 17q12 microdeletion syndrome; thus, our findings extend the prenatal phenotypic spectrum of this syndrome.

Single-Nucleotide Variants Detected in Fetuses with CH

In recent years, with the decreasing cost and increasing application of next-generation sequencing for postnatal diagnosis, the focus has shifted to its application for prenatal diagnosis, with yields of 8.5–10% for unselected fetal anomalies [Wou et al., 2018; Felice et al., 2019; Petrovski et al., 2019]. In 2020, the ACMG recommended exome sequencing for fetuses with ultrasound anomalies when standard CMA and karyotyping fail to yield a definitive diagnosis [Monaghan et al., 2020]. Several studies have provided evidence that fetal exome sequencing may yield a genetic diagnosis in pregnancies where CH is observed [Ples et al., 2018; Bourque et al., 2019; Petrovski et al., 2019; Pan et al., 2020; Sparks et al., 2020; Tolusso et al., 2021]. In a study by Sparks et al. [2020], WES was performed after nondiagnostic karyotyping or CMA. Of the 29 cases with increased NT or CH, nine (31%) had a diagnostic variant. Petrovski et al. [2019] identified compound heterozygous FLVCR2 mutations in one case of recurrent fetal CH by WES and suggested that for cases with recurrent fetal ultrasonographic findings, WES may be a useful approach for women who have already undergone a diagnostic procedure. In our cohort, we identified one case of recurrent fetal CH concurrent with multiple structural anomalies using trio-WES [Sun et al., 2021], which also supports this view.

Workflow Recommendation for Prenatal Genetic Diagnosis of Fetal CH

The overall detection performance of CMA and karyotyping in our study was similar. For cases with small pathogenic CNVs, CMA was superior to karyotyping but was inferior to the traditional method for cases with low-level mosaicism. Given the main genetic etiological features found in our study and previous studies, we recommend that for patients who undergo invasive prenatal diagnosis of fetal CH, an RAD approach, such as QF-PCR [Pan et al., 2016] or PNBOBsTM [Jiang et al., 2021], should be given priority to rapidly identify or exclude common chromosomal aneuploidy abnormalities, which can clarify most of the genetic causes of fetal CH and avoid the risk of cell culture failure and the long turnaround time of karyotyping. For CVS, when karyotyping and/or RAD testing suggest mosaicism, interphase FISH testing of uncultured amniotic fluid cells is recommended. For cases undiagnosed by RAD or karyotyping, a combination of CMA and WES should be considered to identify genomic or monogenic disorders in the presence of additional structural abnormalities or recurrent fetal CH.

To the best of our knowledge, this study is the first to analyze and compare the detection performance of CMA and karyotyping for the diagnosis of fetal CH in a Chinese cohort. Based on our findings, we propose a more efficient and accessible diagnostic strategy. Nevertheless, our study had a few limitations. The main limitation is that WES was not applied to most cases with non-diagnostic CMA or karyotyping results, owing to cost or other reasons, which may have resulted in a lower overall detection rate. Further studies are required to determine the usefulness of exome sequencing for CH unexplained by standard genetic testing. Second, the robustness of our proposed strategy needs to be further validated in an independent prospective study. Finally, a long-term follow-up will be needed to monitor for live births without diagnostic genetic variants in our cohort.

We thank the patients and their families for their participation.

This study protocol was reviewed and approved by the Ethical Review Committee of the Women and Children’s Hospital, School of Medicine, Xiamen University [approval number KY-2017-059]. Each participant provided written informed consent in compliance with the Declaration of Helsinki before inclusion in the present study.

The authors have no conflicts of interest to declare.

This study was funded by the Medical Innovation Project of Fujian Province (Grant No. 2021CXB025) and the Lin Qiaozhi Scientific Research Project of Women and Children’s Hospital, School of Medicine, Xiamen University (grant No. FYLQZ2020002).

Yulin Zhou drafted the manuscript. Yanhong Zhang curated the ultrasound examination results. Lili Wu reviewed the patient’s medical records. Xingxiu Lu and Yunsheng Ge performed and curated the karyotype analysis results. Yasong Xu curated the results of the CMA and WES, and Yu Jiang reviewed and revised the manuscript. All authors have read and approved the final manuscript.

The raw data that support the findings of this study are not publicly available due to ethical restrictions and the legal framework of China.

Additional Information

Y. Zhou, X. Lu, and Y. Zhang contributed equally to this work.

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