Cancer in 22q11.2 deletion syndrome: A case report and literature review.

Clinically, the 22q11.2 deletion syndrome (22q11.2DS) is considered the most commonly detected microdeletion syndrome. Hepatoblastoma is the most prevalent malignant liver cancer in childhood. However, cases of hepatoblastoma in children with 22q11.2DS have only been reported in four patients. In this report, we present a-13-year-old male treated at our center due to growth retardation, and later diagnosed with hepatoblastoma. Whole genome sequencing (WGS) identified 22q11.2DS. Chromosomal microarray analysis (CMA) of peripheral blood sample showed a 2.9 Mb deletion of chromosome 22q11.2. While underlying mechanisms remain unclear, our literature review suggests that patients with 22q11.2DS may show an elevated risk of malignancy. After reviewing 21 previously reported cases, we identified 33 individuals with both cancer and 22q11.2 DS or DiGeorge syndrome. Of these cases, 7 out of 33 (21%) were hematologic tumors, while 26 out of 33 (78%) were solid tumors.

Chromosomal abnormalities detected by chromosomal microarray analysis and pregnancy outcomes of 4211 fetuses with high-risk prenatal indications.

With the gradual liberalization of the three-child policy and the development of assisted reproductive technology in China, the number of women with high-risk pregnancies is gradually increasing. In this study, 4211 fetuses who underwent chromosomal microarray analysis (CMA) with high-risk prenatal indications were analysed. The results showed that the overall prenatal detection rate of CMA was 11.4% (480/4211), with detection rates of 5.82% (245/4211) for abnormal chromosome numbers and 5.58% (235/4211) for copy number variants. Additionally, the detection rates of clinically significant copy number variants were 3.78% (159/4211) and 1.8% (76/4211) for variants of uncertain significance. The detection rates of fetal chromosomal abnormalities were 6.42% (30/467) for pregnant women with advanced maternal age (AMA), 6.01% (50/832) for high-risk maternal serum screening (MSS) results, 39.09% (224/573) with abnormal non-invasive prenatal testing (NIPT) results, 9.21% (127/1379) with abnormal ultrasound results, and 5.1% (49/960) for other indications. Follow-up results were available for 4211 patients, including 3677 (3677/4211, 87.32%) whose infants were normal after birth, 462 (462/4211, 10.97%) who terminated their pregnancy, 51 (51/4211, 1.21%) whose infants were abnormal after birth, and 21 (21/4211, 0.50%) who refused follow-up. The results of this study demonstrate significant variation in the diagnostic rate of chromosomal microarray analysis across different indications, providing valuable guidance for clinicians to assess the applicability of CMA technology in prenatal diagnosis.

Comparative analysis of the application with the combination of CMA and karyotype in routine and late amniocentesis.

PURPOSE: This is a retrospective comparative study. We aimed to analyze the results of karyotype and chromosomal microarray analysis (CMA) of amniotic fluid across different gestational weeks and evaluate the clinical value in prenatal diagnosis, particularly in the late pregnancies. METHODS: Samples from 580 pregnant women of 18-23 weeks of gestation (mid-gestation group) and 196 pregnant women of 24-32 weeks of gestation (late group) were performed both standard G-band karyotype analysis and CMA. RESULTS: Among the 580 pregnant women in the routine group, the most common indications were positive Down's screening (213/580, 36.7%), followed by advanced maternal age (196/580, 33.8%); while fetal structural anomalies on ultrasonography were the top reason for amniocentesis in the late group (56/196, 28.6%). In the routine group, the total detection rate was 12.1% (70/580), of which 4.1% (24/580) were identified by karyotype analysis and 11.2% (65/580) by CMA. The total detection rate was 15.3% (30/196) in the late group, of which 5.1% (10/196) were detected by karyotype analysis, and 14.3% (28/196) by CMA. CONCLUSION: Karyotype analysis and CMA are complementary in detecting chromosomal abnormalities. Amniotic cavity puncture in the karyotype analysis in 18-23 weeks of gestation and 24-32 weeks of gestation is safe and effective, more obvious effect on the latter.

Application of Chromosomal Microarray Analysis in Genetic Reasons of Miscarriage Tissues.

Background: The potential causes of miscarriage are very complex, including genetic, immune, infectious, and endocrine factors. 50%-60% of miscarriages are caused by chromosomal abnormalities. Chromosomal microarray analysis (CMA) is a key tool in this context, capable of detecting not only copy number variations (CNV) but also loss of heterozygosity (LOH). CMA has been used as a tool to investigate the genetic reasons for miscarriage. Methods: In our study, chromosomal microarray analysis (CMA) conducted 1220 miscarriage villous tissues. The results from this technology were used to identify the genetic reasons for miscarriage and evaluated strategies for subsequent pre-pregnancy planning. Results: Here, the abnormality rate of miscarriage was 56.07%(684/1220). The aneuploidy rate accounted for 81.14%(555/684), and was significantly higher in group >35-year-old age. The second most common genetic reason for miscarriage was polyploidy, accounting for 10.09%(69/684). Additionally, we discovered loss of heterozygosity (LOH) in a small percentage of cases, accounting for 2.20%(15/684) reason for miscarriage genetic reasons, due to the advantage of CMA can detect isodisomy (a kind of uniparental disomy). 45 cases (6.58%) with copy number variants, which due to the CMA can detect copy number variations. Conclusion: Our study indicated that miscarriage villous tissues should be performed genetic analysis, seek help from professional genetic counseling.

Amniocentesis in pregnancies at or beyond 24 weeks: An international multicenter study.

BACKGROUND: Amniocentesis for genetic diagnosis is most commonly done between 15 and 22 weeks of gestation, but can be performed at later gestational ages. The safety and genetic diagnostic accuracy of amniocentesis have been well-established through numerous large-scale, multicenter studies for procedures before 24 weeks, but comprehensive data on late amniocentesis remain sparse. OBJECTIVES: To evaluate the indications, diagnostic yield, safety, and maternal and fetal outcomes associated with amniocentesis performed at or beyond 24 weeks of gestation. STUDY DESIGN: We conducted an international, multicenter retrospective cohort study examining pregnant individuals who underwent amniocentesis for prenatal diagnostic testing at gestational ages between 24w0d and 36w6d. The study, spanning from 2011 to 2022, involved nine referral centers. We included singleton or twin pregnancies with documented outcomes, excluding cases where other invasive procedures were performed during pregnancy or if amniocentesis was conducted for obstetric indications. We analyzed indications for late amniocentesis, types of genetic tests performed, their results, and the diagnostic yield, along with pregnancy outcomes and post-procedure complications. RESULTS: Of the 752 pregnant individuals included in our study, late amniocentesis was primarily performed for the prenatal diagnosis of structural anomalies (91.6%), followed by suspected fetal infection (2.3%) and high-risk findings from cell-free DNA screening (1.9%). The median gestational age at the time of the procedure was 28w5d, and 98.3% of pregnant individuals received results of genetic testing before birth or pregnancy termination. The diagnostic yield was 22.9%, and a diagnosis was made 2.4 times more often for fetuses with anomalies in multiple organ systems (36.4%) compared to those with anomalies in a single organ system (15.3%). Additionally, the diagnostic yield varied depending on the specific organ system involved, with the highest yield for musculoskeletal anomalies (36.7%) and hydrops fetalis (36.4%) when a single organ system or entity was affected. The most prevalent genetic diagnoses were aneuploidies (46.8%), followed by copy number variants (26.3%) and monogenic disorders (22.2%). The median gestational age at delivery was 38w3d, with an average of 59 days between the procedure and delivery date. The overall complication rate within two weeks post-procedure was 1.2%. We found no significant difference in the rate of preterm delivery between pregnant individuals undergoing amniocentesis between 24-28 weeks and those between 28-32 weeks, reinforcing the procedure's safety across these gestational periods. CONCLUSIONS: Late amniocentesis, at or after 24 weeks gestation, especially for pregnancies complicated by multiple congenital anomalies, has a high diagnostic yield and a low complication rate, underscoring its clinical utility. It provides pregnant individuals and their providers with a comprehensive diagnostic evaluation and results before delivery, enabling informed counseling and optimized perinatal and neonatal care planning.

Cancer Sample Analysis Utilizing Single-Nucleotide Polymorphism Array and Array Comparative Genomic Hybridization.

Chromosomal microarray, including single-nucleotide polymorphism (SNP) array and array comparative genomic hybridization (aCGH), enables the detection of DNA copy-number loss and/or gain associated with unbalanced chromosomal aberrations. In addition, SNP array and aCGH with SNP component also detect copy-neutral loss of heterozygosity (CN-LOH). Here we describe the chromosomal microarray procedure from the sample preparation using extracted DNA to the scanning of the array chip.

Role of genetic analysis of products of conception and PGT in managing early pregnancy loss.

This article considers the addition of comprehensive 24-chromosomal microarray (CMA) analysis of products of conception (POC) to a standard evaluation for recurrent pregnancy loss (RPL) to help direct treatment towards expectant management versus IVF with preimplantation genetic testing for aneuploidies (PGT-A). The review included retrospective data from 65,333 miscarriages, a prospective evaluation of 378 couples with RPL who had CMA testing of POC and the standard workup, and data from an additional 1020 couples who were evaluated for RPL but did not undergo CMA testing of POC. Aneuploidy in POC explained the pregnancy loss in 57.7% (218/378) of cases. In contrast, the full RPL evaluation recommended by the American Society for Reproductive Medicine identified a potential cause in only 42.9% (600/1398). Combining the data from the RPL evaluation and the results of genetic testing of POC provides a probable explanation for the loss in over 90% (347/378) of women. Couples with an unexplained loss after the standard evaluation with POC aneuploidy accounted for 41% of cases; PGT-A may be considered after expectant management. Conversely, PGT-A would have a limited role in those with a euploid loss and a possible explanation after the standard workup. Categorizing a pregnancy loss as an explained versus unexplained loss after the standard evaluation combined with the results of CMA testing of POC may help identify patients who would benefit from expectant management versus PGT-A.

Large regions of homozygosity in prenatal diagnosis.

Chromosomal microarrays (CMA) incorporate single nucleotide polymorphisms to enable the detection of regions of homozygosity (ROH). Here, we retrospectively analyzed 6288 prenatal cases who performed CMA to explored the clinical implications of large ROH in prenatal diagnosis. We analyzed cases with ROH larger than 10 megabases and reviewed the ultrasound findings; karyotype results and pregnancy follow-up data. Cases with possible imprinting disorders were assessed by methylation-specific multiplex ligation-dependent probe amplification. In total, we identified 50 cases with large ROH and chromosomes 1 and 2 were the most affected. About 59.18% of the ROH cases had ultrasound abnormalities, with the most common findings being ultrasound soft-marker abnormalities. There were seven fetuses had ROH which covered almost the entire chromosome and four had terminal ROH that involved almost the entire long arm of the chromosomes, which indicated uniparental disomy (UPD), of which 70% showed abnormal ultrasound findings. Ten cases with multiple ROH on different chromosomes indicated the third to fifth degree of consanguinity. In this study, we highlighted the clinical relevance of large ROH related to UPD. The analysis of ROH allowed us to gain further understanding of complex cytogenetic and disease mechanisms in prenatal diagnosis.

Prenatal diagnosis of fetuses with absent/hypoplastic nasal bone in second-trimester using chromosomal microarray analysis.

BACKGROUND: Pathogenic copy number variants (pCNVs) are associated with fetal ultrasound anomalies, which can be efficiently identified through chromosomal microarray analysis (CMA). The primary objective of the present study was to enhance understanding of the genotype-phenotype correlation in fetuses exhibiting absent or hypoplastic nasal bones using CMA. METHODS: Enrolled in the present study were 94 cases of fetuses with absent/hypoplastic nasal bone, which were divided into an isolated absent/hypoplastic nasal bone group (n = 49) and a non-isolated group (n = 45). All pregnant women enrolled in the study underwent karyotype analysis and CMA to assess chromosomal abnormalities in the fetuses. RESULTS: Karyotype analysis and CMA detection were successfully performed in all cases. The results of karyotype and CMA indicate the presence of 11 cases of chromosome aneuploidy, with trisomy 21 being the most prevalent among them. A small supernumerary marker chromosome (sSMC) detected by karyotype analysis was further interpreted as a pCNV by CMA. Additionally, CMA detection elicited three cases of pCNVs, despite normal findings in their karyotype analysis results. Among them, one case of Roche translocation was identified to be a UPD in chromosome 15 with a low proportion of trisomy 15. Further, a significant difference in the detection rate of pCNVs was observed between non-isolated and isolated absent/hypoplastic nasal bone (24.44% vs. 8.16%, p < .05). CONCLUSION: The present study enhances the utility of CMA in diagnosing the etiology of absent or hypoplastic nasal bone in fetuses. Further, isolated cases of absent or hypoplastic nasal bone strongly suggest the presence of chromosomal abnormalities, necessitating genetic evaluation through CMA.

Prenatal diagnosis and pregnancy outcomes in fetuses with ventriculomegaly.

Objective: Genetic etiology plays a critical role in fetal ventriculomegaly (VM). However, the studies on chromosomal copy number variants (CNVs) in fetal VM are limited. This study aimed to investigate the chromosomal CNVs in fetuses with mild to moderate VM, and explore its genotype-phenotype correlation. Methods: A total of 242 fetuses with mild to moderate VM detected by prenatal ultrasound were enrolled in our study from October 2018 to October 2022. All cases underwent chromosomal microarray analysis (CMA) and G-banding simultaneously. All VM cases were classified different subgroups according to the maternal age, severity, VM distribution and presence/absence of other ultrasound abnormalities. The pregnancy outcomes and health conditions after birth were followed up. We also performed a pooled analysis regarding likely pathogenic and pathogenic CNVs (LP/P CNVs) for VM. Results: The detection rate of chromosomal abnormalities by karyotyping was 9.1% (22/242), whereas it was 16.5% (40/242) when CMA was conducted (P < 0.05). The total detection rate of chromosomal abnormalities by karyotyping and CMA was 21.1% (51/242). A 12.0% incremental yield of CMA over karyotyping was observed. The detection rate of total genetic variants in fetuses with bilateral VM was significantly higher than in fetuses with unilateral VM (30.0% vs. 16.7%, P = 0.017). No significant differences were discovered between isolated VM and non-isolated VM, or between mild and moderate VM, or between advanced maternal age (AMA) and non-AMA (all P > 0.05). 28 fetuses with VM were terminated and 214 fetuses were delivered: one presented developmental delay and one presented congenital heart disease. The VM cases with both positive CMA and karyotypic results had a higher rate of termination of pregnancy than those with either a positive CMA or karyotypic result, or both negative testing results (P < 0.001). Conclusion: The combination of CMA and karyotyping should be adopted to improve the positive detection rate of chromosomal abnormalities for VM. The total genetic abnormalities detected using both techniques would affect the final pregnancy outcomes. LP/P CNVs at 16p11.2, 17p13, and 22q11.21 were identified as the top three chromosomal hotspots associated with VM, which would enable genetic counselors to provide more precise genetic counseling for VM pregnancies.

Prenatal diagnosis of chromosomal aberrations by chromosomal microarray analysis and pregnancy outcomes of fetuses with polyhydramnios.

OBJECTIVES: To explore the prenatal clinical utility of chromosome microarray analysis (CMA) for polyhydramnios and evaluate the short and long-term prognosis of fetuses with polyhydramnios. METHODS: A total of 600 singleton pregnancies with persistent polyhydramnios from 2014 to 2020 were retrospectively enrolled in this study. All cases received amniocentesis and were subjected to CMA results. All cases were categorized into two groups: isolated polyhydramnios and non-isolated polyhydramnios [with soft marker(s) or with sonographic structural anomalies]. All fetuses were followed up from 6 months to five years after amniocentesis to acquire short and long-term prognosis. RESULTS: The detection rates of either aneuploidy or pathogenic copy number variants in fetuses with non-isolated polyhydramnios were significantly higher than those with isolated polyhydramnios (5.0 vs. 1.5%, p = 0.0243; 3.6 vs. 0.8%, p = 0.0288). The detection rate of total chromosomal abnormalities in the structural abnormality group was significantly higher than that in the isolated group (10.0 vs. 2.3%, p = 0.0003). In the CMA-negative cases, the incidence of termination of pregnancy, neonatal and childhood death, and non-neurodevelopmental disorders in fetuses combined with structural anomalies was significantly higher than that in fetuses with isolated polyhydramnios (p < 0.05). We did not observe any difference in the prognosis between the isolated group and the combined group of ultrasound soft markers. In addition, the risk of postnatal neurodevelopmental disorders was also consistent among the three groups (1.6 vs. 1.3 vs. 1.8%). CONCLUSION: For low-risk pregnancies, invasive prenatal diagnosis of isolated polyhydramnios might be unnecessary. CMA should be considered for fetuses with structural anomalies. In CMA-negative cases, the prognosis of fetuses with isolated polyhydramnios was good, and polyhydramnios itself did not increase the risk of postnatal neurological development disorders. The worse prognosis mainly depends on the combination of polyhydramnios with structural abnormalities.

Genomic insights into inherited bone marrow failure syndromes in a Korean population.

Inherited bone marrow failure syndromes (IBMFS) pose significant diagnostic challenges due to overlapping symptoms and variable expressivity, despite evolving genomic insights. The study aimed to elucidate the genomic landscape among 130 Korean patients with IBMFS. We conducted targeted next-generation sequencing (NGS) and clinical exome sequencing (CES) across the cohort, complemented by whole genome sequencing (WGS) and chromosomal microarray (CMA) in 12 and 47 cases, respectively, with negative initial results. Notably, 50% (n = 65) of our cohort achieved a genomic diagnosis. Among these, 35 patients exhibited mutations associated with classic IBMFSs (n = 33) and the recently defined IBMFS, aplastic anaemia, mental retardation and dwarfism syndrome (AmeDS, n = 2). Classic IBMFSs were predominantly detected via targeted NGS (85%, n = 28) and CES (88%, n = 29), whereas AMeDS was exclusively identified through CES. Both CMA and WGS aided in identifying copy number variations (n = 2) and mutations in previously unexplored regions (n = 2). Additionally, 30 patients were diagnosed with other congenital diseases, encompassing 13 distinct entities including inherited thrombocytopenia (n = 12), myeloid neoplasms with germline predisposition (n = 8), congenital immune disorders (n = 7) and miscellaneous genomic conditions (n = 3). CES was particularly effective in revealing these diverse diagnoses. Our findings underscore the significance of comprehensive genomic analysis in IBMFS, highlighting the need for ongoing exploration in this complex field.

The genetics and clinical outcomes in 151 cases of fetal growth restriction: A Chinese single-center study.

OBJECTIVE: To determine the detection rate of chromosomal abnormalities and pregnancy outcomes in fetuses with intrauterine growth restriction. Study design A total of 151 fetal samples with intrauterine growth restriction were divided into the isolated fetal growth restriction (FGR) group, FGR group with structural malformation, and FGR group with non-structural malformation, according to ultrasound abnormalities. The enrolled patients were divided into an early onset FGR group (<32 weeks) and a late-onset FGR group (≥32 weeks). Chromosomal karyotype and microarray analyses were performed and pregnancy outcomes were monitored. Results The karyotypes of 122 patients were analyzed. Four patients exhibited abnormal chromosome numbers or structures. Variations in copy number were detected in 151 cases; 19 cases were found to have chromosomal abnormalities, with a positivity rate of 12.6 %. There was one trisomy in 18 cases, one trisomy in 21 cases, eight pathogenic copy number variations (CNVs), and nine CNVs of unknown clinical significance. The detection rate of FGR combined with structural malformation was significantly higher than that of isolated FGR group. The detection rate of FGR with structural malformations was significantly higher than that with non-structural malformations. The positive detection rate in the FGR group was similar to that in the FGR group with non-structural malformations, with no statistical significance. Chromosomal abnormalities were detected in 17 patients with early onset FGR, with a positivity rate of 13.8 %. Two cases of chromosomal abnormalities were detected in the late-onset FGR group, with a positive rate of 7.1 %, with no statistical significance. A total of 151 fetuses with FGR were followed up for pregnancy outcomes, resulting in 36 cases of pregnancy termination and 13 cases of loss to follow-up. Among the 102 delivered fetuses, six exhibited delayed growth and development, one presented with hypospadias, and another failed the hearing screening. The remaining 94 fetuses demonstrated normal growth and development. Conclusions This study confirms the value of CNV detection in fetuses and dynamic ultrasound monitoring for fetuses with intrauterine growth restriction.

Case Report: Intellectual disability and borderline intellectual functioning in two sisters with a 12p11.22 loss.

Multiple genome sequencing studies have identified genetic abnormalities as major causes of severe intellectual disability (ID). However, many children affected by mild ID and borderline intellectual functioning (BIF) lack a genetic diagnosis because known causative ID genetic mutations have not been identified or the role of genetic variants in mild cases is less understood. Genetic variant testing in mild cases is necessary to provide information on prognosis and risk of occurrence. In this study, we report two sibling patients who were 5 years 9 months old and 3 years 3 months old and presented to the hospital due to developmental delay. Clinical assessment and chromosomal microarray analysis were performed. The patients were diagnosed with mild intellectual disability (ID) and borderline intellectual functioning (BIF). Genetic analysis identified a loss of 12p11.22, including the OVCH1-AS1, OVCH1, and TMTC1 genes, which was the only variant that occurred in both sisters. Identical variants were found in their father with probable BIF. Neither patient presented any brain structural abnormalities or dysmorphism, and no exogenous factors or parenting problems were reported. Thus, loss of 12p11.22 may be associated with our patients' cognitive impairment. The OVCH1, OVCH1-AS1 and TMTC1 variants identified in this study are the most likely disease-causing genes in the sisters. Our findings may expand as yet limited knowledge on mild ID and BIF causative variants, which would further support the diagnosis even if the severity is mild.

Prenatal Diagnosis by Trio Clinical Exome Sequencing: Single Center Experience.

Fetal anomalies, characterized by structural or functional abnormalities occurring during intrauterine life, pose a significant medical challenge, with a notable prevalence, affecting approximately 2-3% of live births and 20% of spontaneous miscarriages. This study aims to identify the genetic cause of ultrasound anomalies through clinical exome sequencing (CES) analysis. The focus is on utilizing CES analysis in a trio setting, involving the fetuses and both parents. To achieve this objective, prenatal trio clinical exome sequencing was conducted in 51 fetuseses exhibiting ultrasound anomalies with previously negative results from chromosomal microarray (CMA) analysis. The study revealed pathogenic variants in 24% of the analyzed cases (12 out of 51). It is worth noting that the findings include de novo variants in 50% of cases and the transmission of causative variants from asymptomatic parents in 50% of cases. Trio clinical exome sequencing stands out as a crucial tool in advancing prenatal diagnostics, surpassing the effectiveness of relying solely on chromosomal microarray analysis. This underscores its potential to become a routine diagnostic standard in prenatal care, particularly for cases involving ultrasound anomalies.

Diagnostic yield of the chromosomal microarray analysis in turkish patients with unexplained development delay/intellectual disability(ID), autism spectrum disorders and/or multiple congenital anomalies and new clinical findings.

BACKGROUND: Chromosomal microarray analysis is an essential tool for copy number variants detection in patients with unexplained developmental delay/intellectual disability, autism spectrum disorders, and multiple congenital anomalies. The study aims to determine the clinical significance of chromosomal microarray analysis in this patient group. Another crucial aspect is the evaluation of copy number variants detected in terms of the diagnosis of patients. METHODS AND RESULTS: A Chromosomal microarray analysis was was conducted on a total of 1227 patients and phenotype-associated etiological diagnosis was established in 135 patients. Phenotype-associated copy number variants were detected in 11% of patients. Among these, 77 patients 77 (57%, 77/135) were diagnosed with well-recognized genetic syndromes and phenotype-associated copy number variants were found in 58 patients (42.9%, 58/135). The study was designed to collect data of patients in Kocaeli Derince Training and Research Hospital retrospectively. In our study, we examined 135 cases with clinically significant copy number variability among all patients. CONCLUSIONS: In this study, chromosomal microarray analysis revealed pathogenic de novo copy number variants with new clinical features. Chromosomal microarray analysis in the Turkish population has been reported in the largest patient cohort to date.

Selection of prenatal screening with nuchal translucency > 95th centile and below 99th centile: a 4-year observational study with real-world data.

OBJECTIVE: We sought to analyze the genetic outcomes of fetuses with nuchal translucency (NT) > 95th centile, and determine whether prenatal genetic counseling, chromosomal microarray analysis (CMA) or non-invasive prenatal testing (NIPT) are truly beneficial for the outcomes of fetuses with increased NT > 95th centile and below 99th centile. MATERIALS AND METHODS: A total of 535 pregnant women were included in this study, with a fetal NT > 95th centile at 11-13+6 weeks of gestation from January 2017 to December 2020. 324 pregnant women with fetal NT > 95th centile and below 99th centile combined with other risk factors and NT > 99th centile received prenatal diagnostic karyotype analysis and CMA, and 211 pregnant women with fetal isolated increased NT > 95th centile and below 99th centile were selected to carry out NIPT. RESULTS: A total of 211 pregnant women who underwent NIPT were included in the study, NIPT results showed that 8 high-risk cases were confirmed by prenatal diagnosis. Overall, the detection rate of NIPT was 3.79%. A total of 324 pregnant women with fetal NT > 95th centile and below 99th centile, along with other risk factors, and those with fetal NT > 99th centile, received karyotype analysis and CMA for prenatal diagnosis. Among them, a total of 73 genetic abnormalities were detected, including 45 cases of chromosomal aneuploidy, 7 cases of structural abnormalities, and 21 cases of copy number variations (CNVs) with a size of less than 10 Mb. In addition, the 73 women with genetic abnormalities are divided into three groups based on the NT measurement (Group 1: Fetuses with NT > 95th centile and below 99th centile, Group 2: Fetuses with NT > 99th centile, and Group 3: Fetuses with NT > 99th centile). 13.11% (8/61) of pathogenic genetic abnormalities (6 chromosomal aneuploidy, 1 structural abnormality, and 1 likely pathogenic CNV) will be missed if genetic counseling and prenatal genetic testing were not conducted in fetuses with increased NT > 95th centile and below 99th centile combined with other risks. Pathogenic CNVs were the most common abnormalities in group 3, and one likely pathogenic CNV was detected in group 1 and group 3, respectively, and a total of 14 CNVs of unknown clinical significance (VOUS) were detected. CONCLUSIONS: Through this study, we demonstrated that the critical value of NT > 95th centile for invasive detection or NIPT. Invasive testing combined with CMA may be recommended for fetuses with NT > 95th centile and below 99th centile and with other risks. But when isolated NT > 95th centile and below 99th centile, NIPT would be appropriate.

Prenatal chromosomal microarray analysis and karyotyping in fetuses with isolated choroid plexus cyst: A retrospective case-control study.

OBJECTIVES: To evaluate the the diagnostic yield of chromosomal microarray analysis (CMA) in fetuses with isolated CPC (iCPC). METHODS: A total of 315 fetuses with iCPC (iCPC group) and 364 fetuses without abnormal ultrasound findings (control group) were recruited between July 2014 to March 2018. RESULTS: The overall diagnostic yield of chromosomal abnormalities by CMA and karyotyping in iCPC group was up to 4.1 %, higher than 1.4 % in the control group, p < 0.05. The detection rate of pathogenic or likely pathogenic copy number variants (CNVs) with clinical significance by CMA in iCPC group (1.3 %) was higher than in control group (0 %), p < 0.05. According to the type of chromosome abnormalities, the missed diagnosis rate of non-invasive prenatal testing (NIPT) was 1.6 % in our study. CONCLUSIONS: The presence of iCPC on ultrasound examination suggests a potential indication for genetic counseling. Karyotyping and chromosomal microarray analysis may be considered for fetuses with iCPC. It is important to be aware of the limitations of non-invasive prenatal testing, as there is a possibility of residual risk.

Fetal Phenotype of CHARGE Syndrome with a Molecular Confirmation: A Series of 13 Cases.

INTRODUCTION: CHARGE syndrome is an autosomal dominant genetic disorder with known pattern of features. The aim of the study was to present the fetal features of CHARGE syndrome to gain awareness that the antenatal characteristics can be very nonspecific. CASE PRESENTATION: This was a retrospective study of 13 cases with CHARGE syndrome diagnosed by prenatal or postnatal genetic testing and physical examination. Two (15.4%; 2/13) had normal ultrasound scans during pregnancy. One (7.7%; 1/13) with first-trimester cystic hygroma presented intrauterine fetal demise at 16 weeks gestation. The remaining 10 (76.9%; 10/13) cases had abnormal ultrasound features in utero; among these, 1 had an increased nuchal translucency in the first trimester, 5 had second-trimester abnormal ultrasounds including micrognathia, cardiac defects, and facial defects, and 4 third-trimester abnormal ultrasounds including micrognathia, isolated fetal growth restriction, and polyhydramnios. Among the 11 cases with abnormal prenatal ultrasound scans, no fetus could reach the diagnostic criteria of CHARGE syndrome if only based on the results of ultrasound. However, the diagnosis was made in all cases when CHD7 defects were detected. DISCUSSION/CONCLUSION: The CHARGE syndrome presents non-specific abnormal ultrasound markers in utero. Exome sequencing in the genetic workup will aid in prenatal diagnosis of this syndrome.