Prenatal diagnosis of 18p deletion and 8p trisomy syndrome: literature review and report of a novel case.

18p deletion syndrome constitutes one of the most frequent autosomal terminal deletion syndromes, affecting one in 50,000 live births. The syndrome has un-specific clinical features which vary significantly between patients and may overlap with other genetic conditions. Its prenatal description is extremely rare as the fetal phenotype is often not present during pregnancy. Trisomy 8p Syndrome is characterized by heterogenous phenotype, with the most frequent components to be cardiac malformation, developmental and intellectual delay. Its prenatal diagnosis is very rare due to the unspecific sonographic features of the affected fetuses. We present a very rare case of a fetus with multiple anomalies diagnosed during the second trimester whose genomic analysis revealed a 18p Deletion and 8p trisomy Syndrome. This is the first case where this combination of DNA mutations has been described prenatally and the second case in general. The presentation of this case, as well as the detailed review of all described cases, aim to expand the existing knowledge regarding this rare condition facilitating its diagnosis in the future.

The role of confined placental mosaicism in fetal growth restriction: A retrospective cohort study.

OBJECTIVE: To evaluate which cytogenetic characteristics of confined placental mosaicism (CPM) detected in the first trimester chorionic villi and/or placentas in terms of chromosome aberration, cell lineage involved and trisomy origin will lead to fetal growth restriction and low birthweight. METHODS: Cohort study using routinely collected perinatal data and cytogenetic data of non-invasive prenatal testing, the first trimester chorionic villi sampling and postnatal placentas. RESULTS: 215 CPM cases were found. Fetal growth restriction (FGR) and low birthweight below the 10th percentile (BW < p10) were seen in 34.0% and 23.1%, respectively. Excluding cases of trisomy 16, 29.1% showed FGR and 17.9% had a BW < p10. The highest rate of FGR and BW < p10 was found in CPM type 3, but differences with type 1 and 2 were not significant. FGR and BW < p10 were significantly more often observed in cases with meiotic trisomies. CONCLUSION: There is an association between CPM and FGR and BW < p10. This association is not restricted to trisomy 16, neither to CPM type 3, nor to CPM involving a meiotic trisomy. Pregnancies with all CPM types and origins should be considered to be at increased risk of FGR and low BW < p10. A close prenatal fetal monitoring is indicated in all cases of CPM.

Use of the MS-MLPA assay in prenatal diagnosis of Prader-Willi syndrome with mosaic trisomy 15.

OBJECTIVE: We present a prenatal diagnosis strategy of using Methylation-Specific Multiplex Ligation-Dependent Probe Amplification (MS-MLPA) for the detection of maternal uniparental disomy 15/trisomy 15 (UPD(15) mat/T15) mosaicism. CASE REPORT: A 43-year-old woman underwent amniocentesis at 19 weeks of gestation due to a high risk of trisomy 15 (T15) as indicated by non-invasive prenatal testing (NIPT). Cytogenetic analysis revealed a karyotype of 46, XX of cultured amniocytes. Further analysis using copy number variation sequencing (CNV-seq) analysis showed 55 % T15 mosaicism. The second amniocentesis was performed and showed a karyotype of 46, XX and 26 % T15 mosaicism by interphase fluorescence in situ hybridization (FISH). MS-MLPA analysis of uncultured amniocytes showed that the copy number ratio of 15q11-13 ranged from 1.3 to 1.5, and the percentage of methylation was between 70 % and 100 %. MS-MLPA assay of cultured amniocytes showed a copy number ratio of 1 and a methylation percentage of 100 %. Therefore, this fetus was identified to be an UPD(15) mat/T15 mosaicism. The parents decided to terminate the pregnancy. CONCLUSION: MS-MLPA can be used in combination with karyotype and CNV-seq for prenatal diagnosis of NIPT high-risk T15 to avoid missed diagnosis of UPD(15) mat/T15 mosaicism.

[Prenatal diagnosis and outcome of pregnancy for women with high risks by screening of fetal free DNA from peripheral blood samples].

OBJECTIVE: To analyze the results of prenatal diagnosis and outcome of pregnancy for women with a high risk for fetal aneuploidies. METHODS: A total of 747 cases of prenatal diagnosis by amniocentesis due to high risks by non-invasive prenatal testing (NIPT) were selected from January 2015 to March 2022 in the Drum Tower Hospital Affiliated to Nanjing University Medical School. The amniotic fluid samples were subjected to chromosomal karyotyping and/or chromosomal microarray analysis. All cases were followed up by searching the birth information or telephone calls, and the results were recorded. 2 test or F test were used for comparing the difference between the groups. RESULTS: Among the 747 pregnant women with a high risk by NIPT, 387 were true positives, and the overall positive predictive value (PPV) was 51.81%. The PPVs for trisomy 21 (T21), trisomy 18 (T18), trisomy 13 (T13) and sex chromosome aneuploidies (SCA) were 80.24% (199/248), 60% (48/80), 14% (7/50) and 38.97% (106/272), respectively. The PPV for T21 was significantly higher than T18 and T13 (χ2 = 85.216, P < 0.0001). The PPV for other chromosomal aneuploidies and copy number variations (CNVs) were 11.11% (5/45) and 40.74% (22/52), respectively. The PPV for increased X chromosomes was significantly higher than X chromosome decreases (64.29% vs. 22.22%, χ2 = 5.530, P < 0.05). The overall PPV for elder women (≥ 35 years old) was significantly higher than younger women (69.35% vs. 42.39%, χ2 = 49.440, P < 0.0001). For T21 and T18, the PPV of Z ≥ 10 group was significantly higher than that for 3 ≤ Z < 5 group or 5 ≤ Z < 10 group (P < 0.05). Among 52 cases with a high risk for CNVs, the PPV for the ≤ 5 Mb group was significantly higher than the 5 Mb < CNVs < 10 Mb or > 10 Mb groups (60% vs. 30%60% vs. 23.53%, P < 0.05). Among the 387 true positive cases, 322 had opted for induced labor, 53 had delivered with no abnormal growth and development, and 12 were lost during the follow-up. CONCLUSION: The PPVs for common chromosomal aneuploidies are related to the age and Z value of the pregnant women, which were higher in the elder group and higher Z value group. In addition, the PPV is associated with high risk types. The PPV for T21 was higher than T18 and T13, and that for 45,X was lower than 47,XXX, 47,XYY or 47,XXY syndrome. NIPT therefore has relatively high PPVs for the identification of chromosomal CNVs.

[Genetic analysis of the false positive trisomy 7 and false negative trisomy 18 by NIPT-PLUS].

OBJECTIVE: To explore the cause of inconsistency between the results of trisomy 7 by expanded non-invasive prenatal testing (NIPT-PLUS) and trisomy 18 by prenatal diagnosis. METHODS: A pregnant woman who received genetic counseling at Jiaozuo Maternal and Child Health Care Hospital on July 5, 2020 was selected as the study subject. NIPT-PLUS, systematic ultrasound and interventional prenatal testing were carried out. The middle segment and root of umbilical cord, center and edge of the maternal and fatal surface of the placenta were sampled for the validation by copy number variation sequencing (CNV-seq). RESULTS: The result of NIPT-PLUS indicated that the fetus has trisomy 7. Systematic ultrasound has shown multiple malformations including atrioventricular septal defect, horseshoe kidney, and rocker-bottom feet. However, QF-PCR, chromosomal karyotyping analysis, and CNV-seq of amniotic fluid samples all showed that the fetus was trisomy 18. Validation using multiple placental samples confirmed that the middle segment of the umbilical cord contains trisomy 18, the center of the placenta contained trisomy 7, and other placental sites were mosaicism for trisomy 7 and trisomy 18. Notably, the ratio of trisomy 18 became lower further away from the umbilical cord. CONCLUSION: The false positive results of trisomy 7 and false negative trisomy 18 by NIPT-PLUS was probably due to the existence of placental mosaicism. Strict prenatal diagnosis is required needed aneuploidy is detected by NIPT-PLUS to exclude the influence of placental mosaicisms.

Correlation between telomere shortening in maternal peripheral blood and fetal aneuploidy.

BACKGROUND: This study aimed to assess whether maternal telomere length is a more accurate predictor of trisomy 21 than maternal age while also exploring the factors influencing maternal and fetal telomere length. METHODS: Forty mothers with fetuses carrying extra maternal copies of chromosome 21 were defined as trisomy 21 cases, and 18 mothers with normal karyotype fetuses were defined as controls. Telomere lengths of maternal blood lymphocytes and amniotic fluid cells were determined using real-time polymerase chain reaction. Fetal and maternal telomere lengths were compared between the two groups. Moreover, we analyzed the factors influencing maternal and fetal telomere length in the trisomy 21 pedigree. A logistic regression model was used to analyze the correlation between maternal telomere length and trisomy 21 risk. In addition, receiver operating characteristic (ROC) curve analysis was used to determine the accuracy of using maternal telomere length as an indicator of trisomy 21 risk. RESULTS: The study revealed that both maternal and fetal telomere lengths were significantly shorter in trisomy 21 cases than in the controls. In the trisomy 21 group, the maternal age, occupation, and nationality showed no significant correlation with their telomere length; fetal telomere length exhibited a positive correlation with maternal telomere length. Furthermore, maternal telomere length shortening is associated with trisomy 21 (OR = 0.311; 95% CI, 0.109-0.885, P < 0.05). The results of ROC curve analysis indicated that a combined assessment of maternal age and maternal telomere length predicted fetal chromosome trisomy more effectively than a single assessment (area under the curve 0.808, 95% CI, 0.674-0.941, P < 0.001). CONCLUSION: Maternal age combined with maternal telomere length proved to be a superior predictor of trisomy risk. Additionally, maternal telomere length was found to influence fetal telomere length.

Relationships among maternal monosomy X mosaicism, maternal trisomy, and discordant sex chromosome aneuploidies.

OBJECTIVE: To explore the impact of maternal factors on the false-positive fetal sex chromosome aneuploidies (SCAs) results obtained through noninvasive prenatal screening (NIPS). METHODS: We retrospectively analyzed pregnant women with high-risk SCAs as revealed using NIPS between January 2017 and December 2022. Clinical data such as results of invasive prenatal diagnoses, copy number variation sequencing (CNV-seq) and pregnancy outcomes were analysed. RESULTS: Overall, 177 (0.6 %) women with SCA-positive results were collected from 27,941 patients who had undergone NIPS. Among them, 110 (62.2 %) pregnant women chose prenatal diagnosis and 39 (35.5 %) cases were confirmed. For the women with monosomy X false-positive results from the NIPS, 53.1 % (17/32) were found to be maternal mosaicism monosomy X. In cases with 47, XXX false-positive results, 60 % (6/10) of them were maternal 47,XXX (5 cases) or maternal mosaicism 47,XXX (1 case). One (1/6, 16.7 %) case of maternal mosaicism monosomy X was detected in the false positive results of 47, XXY/47, XYY revealed. The incidence rate of maternal sex chromosome abnormalities was positively correlated with the Z-score of ChrX. When the Z-score of ChrX ≥ 15, more than 50 % of pregnant women were found to be maternal sex chromosome abnormalities, and when Z-score ≥ 30, the incidence rate was as high as 100 %. CONCLUSIONS: Maternal monosomy X mosaicism and trisomy X respectively played an important role in the discordance of 45, X and 47, XXX revealed by NIPS. CNV-seq was recommended for the pregnant women at risk of maternal sex chromosome abnormalities, which could help clinicians to provide more accurate and efficient advice during genetic counseling and to guide appropriate prenatal diagnosis strategy for the next pregnancy.

Combined Z-scores to assess the impact of rare autosomal trisomies that results in non-invasive prenatal screening on pregnancy outcomes.

OBJECTIVE: This study aimed to combine Z-scores to evaluate the effects of rare autosomal trisomies (RATs) in non-invasive prenatal screening (NIPS) on pregnancy outcomes at a single center. METHODS: We retrospectively collected the clinical data of women with high-risk RATs results using NIPS at a single center between January 2017 and December 2021. NIPS-positive results were separated into three groups based on the Z-value of RATs (Group1: 6 ≤ Z < 10; Group2: 10 ≤ Z < 15; Group 3: Z ≥ 15). Pregnancy outcomes of women with RATs were compared with the low-risk NIPS group. RESULTS: Overall, 83 RATs were identified in 23,321 NIPS results at our center. Prenatal diagnosis was conducted for 55 patients, and no case was confirmed, with a positive predictive value (PPV) of zero. Fifteen of these patients had adverse pregnancy outcomes, including delivered preterm and/or birth weight (9/15, 60.0 %), structural abnormalities (4/15, 26.7 %), miscarriage (1/15, 6.7 %), and intrauterine death (1/15, 6.7 %). There were 8 (8/22, 36.4 %) adverse pregnancy outcomes in Group 3, which was significantly higher than that in the low-risk NIPS group (p < 0.01). No significant difference was observed between the control group and Group 1 and Group 2 (p > 0.01). CONCLUSIONS: Clinicians should pay more attention to the RATs results when the Z-score is ≥ 15. The data are available for clinicians to guide the prenatal diagnosis of RATs and pregnancy management.

Identification of Fetuses at Increased Risk of Trisomies in the First Trimester Using Axial Planes.

INTRODUCTION: The measurement of nuchal translucency (NT) is crucial for assessing risk of aneuploidies in the first trimester. We investigate the ability of NT assessed by a transverse view of the fetal head to detect fetuses at increased risk of common aneuploidies at 11-13 weeks of gestation. METHODS: We enrolled a nonconsecutive series of women who attended our outpatient clinic from January 2020 to April 2021 for aneuploidy screening by means of a first trimester combined test. All women were examined by operators certified by the Fetal Medicine Foundation. In each patient, NT measurements were obtained both from the median sagittal view and transverse view. We calculated the risk of aneuploidy using NT measurements obtained both with sagittal and axial scans, and then we compared the results. RESULTS: A total of 1,023 women were enrolled. An excellent correlation was found between sagittal and transverse NT measurements. The sensitivity and specificity of the axial scan to identify fetuses that were deemed at risk of trisomy 21 using standard sagittal scans were 40/40 = 100.0% (95% confidence interval [CI]: 91.2-100.0) and 977/983 = 99.4% (95% CI: 98.7-99.7), respectively. The sensitivity and specificity of the axial scan to identify fetuses at risk of trisomy 13 or 18 were 16/16 = 100.0% (95% CI: 80.6-100.0) and 1,005/1,007 = 99.8% (95% CI: 99.3-99.9). CONCLUSIONS: When the sonogram, a part of combined test screening, is performed by an expert sonologist, axial views can reliably identify fetuses at increased risk of trisomies without an increase in false negative results.

Comprehensive phenotyping of fetuses with trisomy 18: a perinatal center experience.

Trisomy 18 is the second most common aneuploidy after trisomy 21. It presents with varying degrees of heterogeneous clinical phenotypes involving multiple organ systems, with a high mortality rate. Clinical assessment of fetal trisomy 18 is always challenging. In this study, we describe the phenotypes of the fetuses with trisomy 18 from a perinatal cohort. We reviewed fetuses with trisomy 18 in referrals for perinatal autopsy over the period of 15 years. A detailed phenotyping of the fetuses with trisomy 18 was executed by perinatal autopsy. Appropriate fetal tissues were obtained to perform genomic testing. We observed trisomy 18 in 16 fetuses (2%) in our cohort of 784 fetal/neonatal losses and a perinatal autopsy was performed on all of them. Abnormal facial profile was the most frequent anomaly (10/16, 62%) followed by anomalies of the extremities (9/16, 56%), and cardiac defects (6/16, 37%). We also observed esophageal atresia, diaphragmatic hernia, and neural tube defect. The study represents one of the largest cohorts of trisomy 18 from a perinatal center from a developing country and highlights the clinical heterogeneity attributed to trisomy 18. We also report a recurrence of trisomy 18 in a family.

Mosaic trisomy 5 in amniotic fluid in a live fetus with Ebstein anomaly and complete trisomy 5 in chorionic villus sampling.

Complete trisomy 5 is a rare and lethal abnormality. Mosaic trisomy 5 presents in various phenotypes, ranging from a clinically normal fetus to fetuses presenting uterine growth restriction, congenital heart anomalies, multiple dysmorphic features and psychomotor development abnormalities. Although rare, there are cases of a normal psychomotor development regardless of the associated low fetal growth frequently associated with mosaic trisomy 5. This is the first case report to date of a live fetus with complete trisomy 5 reported in chorionic villus sampling and mosaic trisomy 5 in amniotic fluid with a concomitant Ebstein anomaly. Diagnosis of mosaic trisomy 5 represents a challenge for the clinical team and patients, as the information regarding this syndrome is scarce and based mostly on case reports of liveborns, which may introduce a selection bias when counselling the parents.

Low-level mosaic trisomy 21 at amniocentesis in a pregnancy associated with cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes, perinatal progressive decrease of the aneuploid cell line and a favorable fetal outcome.

OBJECTIVE: We present low-level mosaic trisomy 21 at amniocentesis in a pregnancy with a favorable fetal outcome. CASE REPORT: A 34-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XY,+21 [7]/46,XY [33]. At 23 weeks of gestation, repeat amniocentesis revealed a karyotype of 47,XY,+21 [4]/46,XY [22], and cord blood sampling revealed the karyotype of 47,XY,+21 [5]/46,XY [35]. The parental karyotypes were normal. Quantitative fluorescent polymerase chain reaction (QF-PCR) analysis on uncultured amniocytes and parental bloods excluded UPD 21, array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed the result of arr 21q11.2q22.3 × 2.3, consistent with 30% mosaicism for trisomy 21. Interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes revealed 43.8% (35/80 cells) mosaicism for trisomy 21. The woman was advised to continue the pregnancy, and a phenotypically normal 3,340-g male baby was delivered at 39 weeks of gestation. The cord blood had a karyotypes of 46,XY (40/40 cells). QF-PCR on placenta showed mosaic trisomy 21. When follow-up at age three months, the neonate was normal in phenotype and development. FISH analysis on buccal mucosal cells showed 9% (10/101 cells) mosaicism for trisomy 21, compared with 0% (0/100 cells) in the normal control. CONCLUSION: Low-level mosaic trisomy 21 at amniocentesis can be associated with cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes, perinatal progressive decrease of the aneuploid cell line and a favorable fetal outcome.

Double Trisomy 16 and 22 Clinically Mimic Partial Hydatidiform Mole in a Case of Subsequent Pregnancy Loss.

A case of double trisomy 16 and 22 in the second pregnancy loss is presented. DNA analyses (short tandem repeats genotyping) of miscarriage specimen was indicated because of ultrasound suspicion of partial hydatidiform mole. After the partial hydatidiform mole exclusion, further DNA analyses focused on the most common aneuploidies causing pregnancy loss, detected double trisomy 16 and 22 in the product of conception. The couple was referred to clinical genetic consultation and normal parental karyotypes were proved. For further explanatory purposes, archived material from the first pregnancy loss was analyzed and trisomy of chromosome 18 was detected. By comparison of allelic profiles of the mother, father, and both losses, the maternal origin of all aneuploidies was proven what can be attributed to frequent meiosis errors, probably due to advanced maternal age (44 years at the first loss and 45 years at the second loss). In conclusion, aneuploidies can mimic partial hydatidiform mole. Genetic analysis is helpful on the one hand to rule out partial hydatidiform mole and on the other hand to identify aneuploidies and in this way to determine the cause of miscarriage.

Unusual Trisomy X Phenotype Associated with a Concurrent Heterozygous 16p11.2 Deletion: Importance of an Integral Approach for Proper Diagnosis.

Trisomy X is the most frequent sex chromosome anomaly in women, but it is often underdiagnosed postnatally because most patients do not show any clinical manifestation. It is estimated that only 10% of patients with trisomy X are diagnosed by clinical findings. Thus, it has been proposed that the clinical spectrum is not yet fully delimited, and additional uncommon or atypical clinical manifestations could be related to this entity. The present report describes a female carrying trisomy X but presenting atypical manifestations, including severe intellectual disability, short stature, thymus hypoplasia, and congenital hypothyroidism (CH). These clinical findings were initially attributed to trisomy X. However, chromosome microarray analysis (CMA) subsequently revealed that the patient also bears a heterozygous 304-kb deletion at 16p11.2. This pathogenic copy-number variant (CNV) encompasses 13 genes, including TUFM. Some authors recommend that when a phenotype differs from that described for an identified microdeletion, the presence of pathogenic variants in the non-deleted allele should be considered to assess for an autosomal recessive disorder; thus, we used a panel of 697 genes to rule out a pathogenic variant in the non-deleted TUFM allele. We discuss the possible phenotypic modifications that might be related to an additional CNV in individuals with sex chromosome aneuploidy (SCA), as seen in our patient. The presence of karyotype-demonstrated trisomy X and CMA-identified 16p11.2 deletion highlights the importance of always correlating a patient's clinical phenotype with the results of genetic studies. When the phenotype includes unusual manifestations and/or exhibits discrepancies with that described in the literature, as exemplified by our patient, a more extensive analysis should be undertaken to enable a correct diagnosis that will support proper management, genetic counseling, and medical follow-up.