https://orcid.org/0000-0003-2924-399X
Abstract
Background
Previous studies have shown a strong correlation between fetal nasal bone hypoplasia and chromosomal anomaly; however, there is little knowledge on the associations of fetal nasal bone hypoplasia with chromosomal microdeletions and microduplications until now. Chromosomal microarray analysis (CMA) is a high-resolution molecular genetic tool that is effective to detect submicroscopic anomalies including chromosomal microdeletions and microduplications that cannot be detected by karyotyping. This study aimed to examine the performance of CMA for the prenatal diagnosis of nasal bone hypoplasia in the second and third trimesters.
Subjects and Methods
A total of 84 pregnant women in the second and third trimesters with fetal nasal bone hypoplasia, as revealed by ultrasound examinations, were enrolled, and all women underwent karyotyping and CMA with the Affymetrix CytoScan 750K GeneChip Platform. The subjects included 32 cases with fetal nasal bone hypoplasia alone and 52 cases with fetal nasal bone hypoplasia combined with other ultrasound abnormalities, and the prevalence of genomic abnormality was compared between these two groups.
Results
Karyotyping detected 21 cases of chromosomal anomaly in the 84 study subjects (21/84, 25%), including trisomy 21 (14 cases), trisomy 18 (3 cases), 46, del (4)(p16) karyotype (2 cases), 47, XYY syndrome (1 case) and 46, XY, del (5) (p15) karyotype (1 case). CMA detected additional four fetuses with pathogenic copy number variations (CNVs) and six fetuses with uncertain clinical significance (VOUS). No significant difference was detected in the prevalence of genomic abnormality in fetuses with nasal bone hypoplasia alone and in combination with other ultrasound abnormalities (13/32 vs 18/52; χ2 = 0.31, P > 0.05). The pregnancy was terminated in 21 fetuses detected with chromosomal abnormality and 4 fetuses detected with pathogenic CNVs. Among the other six fetuses detected with VOUS, the parents chose to continue the pregnancy, and the newborns all had normal clinical phenotypes.
Conclusion
In addition to chromosomal abnormalities identified in 21 fetuses by karyotyping, CMA detected additional 10 fetuses with abnormal CNVs (10/84, 11.9%) in the study population. CMA is a promising powerful tool for prenatal diagnosis that may provide valuable data for the accurate assessment of fetal prognosis and the decision of pregnancy continuation during the prenatal clinical counseling.
Introduction
Ultrasonography is an important part of prenatal screening.Citation1 Currently, the common genetic ultrasound soft markers include nuchal translucency thickening, nasal bone hypoplasia and shortening of fetal long bones,Citation2 and these soft markers show diverse values in prediction of fetal abnormalities.Citation3
Fetal nasal bone hypoplasia is defined as absence or dysplasia of the nasal bone on the mid–sagittal plane in the second trimester as detected by ultrasonography.Citation4 Previous studies have shown a strong correlation between fetal nasal bone hypoplasia and chromosomal anomaly,Citation5–Citation7 and the highest incidence of nasal bone hypoplasia is detected in fetuses with aneuploidy,Citation8–Citation10 notably in Down syndrome (trisomy 21).Citation5,Citation11,Citation12 However, there is little knowledge on the associations of fetal nasal bone hypoplasia with chromosomal microdeletions and microduplications until now.Citation13,Citation14
Chromosomal microarray analysis (CMA) is a high-resolution molecular genetic tool that is effective to detect chromosomal microdeletions and microduplications that cannot be detected by karyotyping. This retrospective cohort study aimed to examine the performance of CMA for the prenatal diagnosis of nasal bone hypoplasia in the second and third trimesters.
Subjects and Methods
Subjects
We collected 84 fetuses diagnosed with fetal nasal bone hypoplasia, as revealed by ultrasound examinations at the Center of Prenatal Diagnosis, Fujian Maternity and Child Health Hospital (Fuzhou, China) during the period from December 2016 through December 2018. The pregnant women had ages of 20 to 41 years, and had gestational ages of 18 to 36 weeks. All pregnant women underwent karyotyping and CMA with amniotic fluid and umbilical blood samples. Among the 84 prenatal samples collected, there were 53 amniotic fluid samples and 31 umbilical blood samples. The subjects included 32 cases with fetal nasal bone hypoplasia alone and 52 cases with fetal nasal bone hypoplasia combined with other ultrasound abnormalities. The subjects’ medical records were retrospectively reviewed.
Karyotyping
Chromosome karyotyping analysis was routinely performed as described previously.Citation15 Briefly, amniotic fluid and umbilical cord blood samples were collected, cultured, harvested and subjected to G-band karyotype analysis, with additional C- and N-band karyotyping performed if required. Amniocentesis was performed at 18 to 24 weeks of gestation, while cordocentesis was performed after 24 weeks of gestation. Karyotyping was done on a Leica GSL-120 automatic slide scanning system (Leica Biosystems Richmond, Inc.; Richmond, IL, USA). Each sample was detected for 40 karyotypes, with 5 used for banding, and additional detections were performed if required.
CMA
Approximately 10 mL of amniotic fluid and umbilical cord blood specimens were collected, centrifuged and the sediment was collected. Genomic DNA was isolated from amniotic fluid cells using the QIAamp DNA Blood Mini Kit (Qiagen; Hilden, Germany). All CMA analyses were performed using the Affymetrix CytoScan 750K GeneChip Platform (Affymetrix, Santa Clara, CA, USA) with copy number variation (CNV) and single nucleotide polymorphism (SNP) probes following the manufacturer’s instructions. All CMA data were processed with the software Chromosome Analysis Suite version 3.2 (Affymetrix; Santa Clara, CA, USA), and the analysis was capable of detecting CNVs with clinically relevant genes and genome-wide backbone resolution of greater than 100 kb. The CNVs were interpreted using public databases, including the database of genomic variants (http://dgv.tcag.ca/dgv/app/home), the DECIPHER database (https://decipher.sanger.ac.uk/), Online Mendelian Inheritance in Man (https://www.omim.org/), International Standards for Cytogenomic Arrays (ISCA) Consortium (http://www.iscaconsortium.org/) and the Cytogenomics Array Group CNV Database (CAGdb database; http://www.cagdb.org/), as well as National Center for Biotechnology Information (NCBI). All CNVs detected were classified as pathogenic, benign or variants of uncertain clinical significance (VOUS) according to the American College of Medical Genetics standards and guidelines.Citation16 In addition, the peripheral blood was sampled from the parents of fetuses with VOUS for CMA analysis, and the type of CNVs was validated by means of CMA and pedigree analysis.
Ethical Consideration
This study was approved by the Ethics Review Committee of Fujian Maternity and Child Health Hospital. All participants were informed of the purpose, experimental procedures and potential risks of the study, and signed an informed consent. All experiments were performed in accordance with the Declaration of Helsinki and National Regulations for Ethics of Biological Medical Sciences on Human Studies released by Ministry of Health, China.
Statistical Analysis
All statistical analyses were performed using the statistical software SPSS version 22.0 (SPSS, Inc.; Chicago, IL, USA). Differences of proportions were tested for statistical significance with chi-square test or Fisher’s exact test, and a P value of <0.05 was considered statistically significant.
Results
Chromosome Karyotyping
There were 84 prenatal samples with karyotyping analysis, including 53 amniotic fluid specimens and 31 cord blood specimens. G-band karyotype analysis detected 21 cases of chromosomal anomaly in the 84 study subjects (21/84, 25%), and fetal chromosomal anomaly included trisomy 21 (14 cases), trisomy 18 (3 cases), 46, del (4)(p16) karyotype (2 cases), 47, XYY syndrome (1 case) and 46, XY, del (5) (p15) karyotype (1 case). shows the karyotype, ultrasound findings and pregnant outcomes in fetuses with chromosomal anomaly.
Table 1 Chromosome Karyotyping Detects Abnormal Karyotypes in 21 Fetuses with Nasal Bone Hypoplasia
CNVs Detected by CMA
All fetuses in our study were further tested for chromosomal anomaly using CMA. In addition to the 21 fetuses identified with chromosomal anomaly described above, CMA detected additional CNVs in 10 fetuses, including 4 fetuses with pathogenic CNVs and 6 fetuses with VOUS. The pathogenic CNVs included 15q13.2q13.3 microdeletion, 16p12.2 microdeletion, 17p12 microdeletion and 15q24.1q24.2 microdeletion, and VOUS included 15q13.3 microduplication, 16p13.13p13.12 microduplication, 2p22.3 microduplication, 15q11.2 microdeletion, Xq21.33 microduplication and 15q26.1 microdeletion ().
Table 2 Chromosomal Microarray Analysis Detects Copy Number Variations in 10 Fetuses with Nasal Bone Hypoplasia
There was no significant difference was detected in the prevalence of genomic abnormality in fetuses with nasal bone hypoplasia alone and in combination with other ultrasound abnormalities (13/32 vs18/52; χ2 = 0.31, P > 0.05) ().
Table 3 Comparison of Genomic Abnormality Prevalence Between Fetuses with Nasal Bone Hypoplasia Alone and in Combination with Other Ultrasound Abnormalities
Pregnant Outcomes
All 84 fetuses were successfully followed up. The pregnancy was terminated in 21 fetuses detected with chromosomal abnormality and 4 fetuses detected with pathogenic CNVs. Among the other six fetuses detected with VOUS, five cases were had pedigree analysis, the parents chose to continue the pregnancy, and the newborns all had normal clinical phenotypes ( and ).
Discussion
The genetic etiology of fetal nasal bone hypoplasia has been extensively investigated,Citation17 and a close association has been identified between fetal nasal bone hypoplasia and chromosomal abnormality,Citation5–Citation7 notably with aneuploidy.Citation8–Citation10 In this study, we detected trisomy 21 in 14 cases, trisomy 18 in 3 cases and 47, XYY syndrome in one case among the 84 fetuses with nasal bone hypoplasia, and the prevalence of aneuploidy was 21.43% in the study subjects. In a previous study recruiting 239 fetuses at gestational ages of 15 to 20 weeks, absence of a nasal bone was detected in 37% of fetuses with trisomy 21 and 0.5% of normal fetuses, yielding a likelihood ratio of 83, and the findings suggested that absence of a nasal bone is the most sensitive ultrasound soft marker for trisomy 21.Citation18 Sonek and colleagues reported a 1% prevalence of absent nasal bones in normal fetuses and 37% prevalence in fetuses with trisomy 21 in the second trimester, yielding a positive likelihood ratio of 41 and negative likelihood ratio of 0.64, and they concluded that absence of a nasal bone shows a high predictive value for trisomy 21.Citation19 In the current study, we detected a lower prevalence of aneuploidy in the subjects as compared to previous reports. In our center, if the pregnant women harboring aneuploidy fetuses present a high risk of trisomy 21 as detected by the blood testing or non-invasive prenatal test (NIPT) in the first trimester, and they may lose the timing to directly receive prenatal diagnosis by amniocentesis without ultrasound screening. If the fetus is definitively diagnosed with aneuploidy, induction of labor is given, and the diagnosis of aneuploidy fetuses with absence of a nasal bone may be missed. Therefore, the prevalence of aneuploidy detected in the fetuses with nasal bone hypoplasia was lower in this study than previous reports.
CMA has a high resolution to detect microdeletions and microduplications,Citation20–Citation22 which supplements the shortcomings of conventional G-band karyotyping in misdiagnosis of small chromosomal segments.Citation23 In this study, CMA detected microdeletions and microduplications in 10 fetuses with nasal bone hypoplasia, which increased the detection of genomic abnormalities by 11.9% as compared to G-banding karyotype analysis. We detected no significant difference in the prevalence of genomic abnormality in fetuses with nasal bone hypoplasia alone and in combination with other ultrasound abnormalities (P > 0.05), which is inconsistent with previous reports.Citation24–Citation26 It was reported that absence of a nasal nose, complicated with other fetal organ and structural abnormalities increased the risk of chromosomal abnormalities.Citation6,Citation7 However, we detected a higher prevalence of genomic abnormality in fetuses with nasal bone hypoplasia alone than those with nasal bone hypoplasia and other ultrasound abnormalities (13/32 vs18/52). This may be because karyotyping analysis alone was employed in previous studies, while both karyotyping and CMA were performed in this study, thereby resulting in a rise in the detection of genomic abnormality; in addition, this variation may be attributed to the study subjects. Nevertheless, the prevalence of chromosomal abnormality was higher in fetuses with nasal bone hypoplasia and other ultrasound abnormalities (28.85%) than in those with nasal bone hypoplasia alone (18.75%), which is in agreement with previous studies.Citation6,Citation7
In this study, we detected CNVs in 10 fetuses with nasal bone hypoplasia, and pathogenic CNVs were identified in four fetuses, including 15q13.2q13.3 microdeletion (1 case), 16p12.2 microdeletion (1 case), 17p12 microdeletion (1 case) and 15q24.1q24.2 microdeletion (1 case). Previous studies have demonstrated that 15q13.2q13.3 microdeletion may cause 15q13.3 microdeletion syndrome, which is mainly manifested by developmental retardation, epilepsy, and finger and toe anomalies and minor facial abnormalities.Citation27–Citation29 In this study, however, only nasal bone hypoplasia was found in the fetus with 15q13.2q13.3 microdeletions on sonography. A susceptibility locus of neurocognitive impairment has been identified in the region of 16p12.2 microdeletions, and the frequency of this susceptibility locus is estimated to be less than 1% in normal populations.Citation30 In the ClinGen database, the haploinsufficiency score of the recurrent 16p12.2 microdeletion is 2, while the overall penetrance is approximately 12%.Citation31 Patients with 16p12.2 microdeletions have diverse clinical manifestations, which mainly include developmental retardation, mild to moderate intellectual disturbance, congenital heart defects and epilepsy.Citation32 However, ultrasound examinations displayed nasal bone hypoplasia alone in the fetus with 16p12.2 microdeletions. 17p12 microdeletion is reported to link with hereditary neuropathy with liability to pressure palsies (HNPP).Citation33 To date, the penetrance of 17p12 microdeletions remains unknown, and many patients carrying 17p12 microdeletions present few and even no clinical symptoms; in addition, approximately 80% of deletions of the PMP22 gene on chromosome 17p12 regions are estimated to be inherited from parents, where haploinsufficiency effect is observed with a score of 3;Citation34 however, only nasal bone hypoplasia was seen in the fetus with 17p12 microdeletions. 15q24.1q24.2 Microdeletion has been identified as a pathogenic factor of 15q24 microdeletion syndrome, which manifests as feeding intolerance, eye abnormality, widening of neck, nasal bone hypoplasia, muscle hypotonia, attention-deficit/hyperactivity disorder and autism.Citation35 In this study, ultrasound displayed fetal growth restriction, ventricular septal defect, pulmonary valve stenosis complicated by incompetence and nasal bone hypoplasia in the fetus with 15q24.1q24.2 microdeletions. These data indicate that chromosome karyotyping is likely to lead to missing diagnosis and misdiagnosis of genomic microstructural abnormality in fetuses with nasal bone hypoplasia detected by ultrasound. Our data suggest that CMA has an extensive range of indications to detect chromosomal microstructural abnormalities and shows a powerful value in prenatal diagnosis.
Nevertheless, there is a difficulty in the interpretation of the clinical significance of CMA detection results, notably in the interpretation of VOUS, and the huge rise in CMA detections interpretation will inevitably increase the burden of validations. Previous studies have shown a 1.1% to 6% detection of VOUS by CMA.Citation36–Citation38 In this study, CMA detected in VOUS in 6 out of 84 fetuses with nasal bone hypoplasia, and the VOUS prevalence (7.14%) was higher than previous reports.Citation36–Citation38 Pedigree analysis confirmed that four cases were h inherited from healthy parents. In cases with VOUS, two cases were detected with neural susceptibility sites, which contained 15q13.3 microduplication and 15q11.2 recurrent region. If the CNVs were verified to be inherited, it would reduce the psychological burden of pregnant women, and pregnant women will be more willing to choose to keep the fetus. Recently, next-generation sequencing has been employed as a novel tool for genetic testing of single-gene mutations and CNVs, which may provide a more comprehensive prenatal genetic diagnosis for fetuses with nasal bone hypoplasia, and provide insights into a better assessment of fetal prognosis.Citation39–Citation41
Prenatal genetic testing determines the decision to terminate pregnancy.Citation42 In the present study, 84 fetuses with nasal bone hypoplasia were all successfully followed up, and pregnancy termination was performed in 21 fetuses detected with chromosomal abnormality and 4 fetuses detected with pathogenic CNVs, while the pregnancy continued in other 6 fetuses detected with VOUS, and these babies all had normal clinical phenotypes after birth. It is therefore considered that CMA may provide valuable data for the accurate assessment of fetal prognosis and risk of disease recurrence and the decision of pregnancy continuation during the prenatal clinical counseling.Citation22,Citation43–Citation45
The present study has some limitations. First, this retrospective analysis was performed in a cohort including 84 fetuses with nasal bone hypoplasia recruited from a single center, and further multicenter studies recruiting more fetuses are needed. Second, not all cases with VOUS were given additional pedigree analyses, which is ineffective to provide better guidance for genetic counseling.
In summary, the results of the present study demonstrate that CMA increases the detection of CNVs in fetuses with nasal bone hypoplasia relative to conventional chromosome karyotyping. It is considered that CMA is a powerful tool used for prenatal diagnosis in fetuses with nasal bone hypoplasia.
Disclosure
The authors declare no conflict of interests.
Additional information
Funding
References
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