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Background To explore the application value of chromosomal microarray analysis (CMA) in prenatal diagnosis. Methods The results of chromosome karyotype analysis and CMA of 477 cases undergoing amniocentesis were analyzed. The results of the no ultrasound abnormality group and the ultrasound abnormality group were compared separately. Within the ultrasound abnormality group, the results of the ultrasound structural malformation group, the ultrasound soft index abnormality group, and other ultrasound abnormality (including abnormal amniotic fluid volume and fetal growth restriction) groups were compared. Results Abnormal chromosome and CMA results were found in a total of 71 cases (15.88%, 71/447), which can be broken down into a total of 23 karyotype abnormalities (5.15%, 23/447), consisting of 18 cases of aneuploidy (4.03%, 18/447), 2 cases of unbalanced chromosome rearrangements (0.44%, 2/447), and 3 cases of chimerism (0.67%, 3/447); 17 cases with detection of pathogenic copy number variations (pCNVs) (3.80%, 17/447); and 31 cases of detection of clinical variants of unknown significance (VOUS) (6.93%, 31/447). CMA detected 3.8% more genetic abnormalities than karyotype analysis (in addition to the abnormalities detected simultaneously by karyotype analysis). Between the no ultrasound abnormality group and the ultrasound abnormality group, there was an extremely significant difference in the detection rate of an abnormal chromosomal karyotype ( P  < 0.01) and of VOUS ( P  < 0.01), but there was no significant difference in the detection rate of pCNV ( P > 0.05). Comparing the ultrasound structural malformation group, the ultrasound soft index abnormality group, and the other ultrasound abnormality group, there were no significant differences in the detection rate of abnormal chromosomal karyotypes ( P > 0.05), pCNV ( P > 0.05) or VOUS ( P > 0.05). Conclusions The detection rate of chromosomal karyotype abnormalities in prenatal diagnosis in cases with no ultrasound abnormalities was higher. For cases with fetal ultrasound structural abnormalities, when compared with traditional karyotype analysis, CMA can improve the detection rate of fetal genetic abnormalities. However, the no ultrasound abnormality group also had a high VOUS abnormality detection rate, so it is necessary to strictly define the CMA indications.

Purpose Congenital heart defects (CHD) are associated with genetic syndromes. Rapid aneuploidy testing and chromosome microarray analysis (CMA) are standard care in fetal CHD. Many genetic syndromes remain undetected with these tests. This cohort study aims to estimate the frequency of causal genetic variants, in particular structural chromosome abnormalities and sequence variants, in fetuses with severe CHD at mid-gestation, to aid prenatal counselling. Methods Fetuses with severe CHD were extracted from the PRECOR registry (2012–2016). We evaluated pre- and postnatal genetic testing results retrospectively to estimate the frequency of genetic diagnoses in general, as well as for specific CHDs. Results 919 fetuses with severe CHD were identified. After exclusion of 211 cases with aneuploidy, a genetic diagnosis was found in 15.7% (111/708). These comprised copy number variants in 9.9% (70/708). In 4.5% (41/708) sequence variants were found that would have remained undetected with CMA. Interrupted aortic arch, pulmonary atresia with ventricular septal defect and atrioventricular septal defect were most commonly associated with a genetic diagnosis. Conclusion In case of normal CMA results, parents should be offered exome sequencing sequentially, if time allows for it, especially if the CHD is accompanied by other structural malformations due to the large variety in genetic syndromes.

Objective This study aims to evaluate the association between ultrasound soft markers and fetal chromosomal abnormalities and to compare the diagnostic efficacy of karyotype analysis versus chromosomal microarray analysis (CMA) for prenatal testing strategy optimization. Materials and methods A retrospective review was conducted on 622 cases receiving prenatal diagnosis for abnormal ultrasound soft markers at our center over three years. All cases underwent chromosomal karyotype analysis and CMA testing. The differences between the results of these two tests, as well as the correlation between genetic testing results and abnormal ultrasound soft markers, were analyzed. Additionally, the pregnancy outcomes and postnatal phenotypes of all cases were monitored. Results The overall prevalence of chromosomal abnormalities was 11.41% (71/622). Echogenic intracardiac focus ( P  = 0.012) and multiple soft markers ( P  < 0.001) exhibited a higher correlation with chromosomal abnormalities, with the latter showing a particularly strong association with aneuploidy ( P  < 0.001). Karyotype analysis identified 63 chromosomal abnormalities, while CMA detected 65, with discordant results observed in 18 cases. Among the cases with chromosomal abnormalities, 11 resulted in live births, and follow-up at ages 3–5 revealed no abnormal phenotypes. Conclusion Prenatal genetic diagnosis is strongly recommended for pregnant women presenting with ultrasound soft markers, particularly multiple markers. Concurrent CMA and karyotype analysis are advocated to minimize the risk of missing pathogenic variants.

This study investigates the clinical application of single-nucleotide polymorphisms (SNP)-based chromosome microarray analysis (CMA) in the etiological diagnosis of fetal congenital heart disease (CHD). We 5,116 amniotic fluid samples collected through amniocentesis from January 2022 to December 2024 in Urumqi, Xinjiang, China. Based on fetal ultrasound findings, structural abnormalities, and specific types, CHD was categorized into four groups: isolated CHD, non-isolated CHD, non-CHD, and a normal group. The incidence of aneuploidies were highest in non-isolated CHD cases (16.91%), approximately five times higher than that in cases with isolated CHD (3.8%) ( P  < 0.001). The incidence of pathogenic copy number variants (CNVs) were similar across groups (2.11%–3.68%). The non-isolated CHD group demonstrated a significantly higher incidence of trisomy 21 (8.82%) and trisomy 18 (5.88%) compared to other groups ( P  < 0.001). Among the pathogenic CNVs, we identified five cases of deletions (22q11.2) in the isolated CHD group, eight losses (15q11.2),and 11 losses (22q11.2) in the normal group. SNP-based CMA enhances the detection of abnormal CNVs in fetuses with CHD, offering medical reference for diagnosing chromosomal etiologies and enabling precise genetic counseling. For clinical practice, SNP-based CMA should be strongly recommended for non-isolated CHD fetuses, and considered as a supplementary test for isolated CHD fetuses.

Copy number variations (CNVs) are the predominant class of structural genomic variations involved in the processes of evolutionary adaptation, genomic disorders, and disease progression. Compared with single-nucleotide variants, there have been challenges associated with the detection of CNVs owing to their diverse sizes. However, the field has seen significant progress in the past 20–30 years. This has been made possible due to the rapid development of molecular diagnostic methods which ensure a more detailed view of the genome structure, further complemented by recent advances in computational methods. Here, we review the major approaches that have been used to routinely detect CNVs, ranging from cytogenetics to the latest sequencing technologies, and then cover their specific features.

Background The belief that genetics plays a major role in the pathogenesis of congenital heart defects (CHD) has grown popular among clinicians. Although some studies have focused on the genetic testing of foetuses with CHD in China, the genotype–phenotype relationship has not yet been fully established, and hotspot copy number variations (CNVs) related to CHD in the Chinese population are still unclear. This cohort study aimed to assess the prevalence of chromosomal abnormalities in Chinese foetuses with different types of CHD. Results In a cohort of 200 foetuses, chromosomal abnormalities were detected in 49 (24.5%) after a prenatal chromosome microarray analysis (CMA), including 23 foetuses (11.5%) with aneuploidies and 26 (13.0%) with clinically significant CNVs. The additional diagnostic yield following whole exome sequencing (WES) was 11.5% (6/52). The incidence of total chromosomal abnormality in the non-isolated CHD group (31.8%) was higher than that in the isolated CHD group (20.9%), mainly because the incidence of aneuploidy was significantly increased when CHD was combined with extracardiac structural abnormalities or soft markers. The chromosomal abnormality rate of the complex CHD group was higher than that of the simple CHD group; however, the difference was not statistically significant (31.8% vs. 23.6%, P = 0.398). The most common CNV detected in CHD foetuses was the 22q11.2 deletion, followed by deletions of 5p15.33p15.31, deletions of 15q13.2q13.3, deletions of 11q24.2q25, deletions of 17p13.3p13.2, and duplications of 17q12. Conclusions CMA is the recommended initial examination for cases of CHD in prenatal settings, for both simple heart defects and isolated heart defects. For cases with negative CMA results, the follow-up application of WES will offer a considerable proportion of additional detection of clinical significance.

Purpose This study aimed to summarize the ultrasound and genetic features in a case series of fetuses presenting vertebral defects, to provide useful information for prenatal counseling and prognostic evaluation. Methods Fetuses with vertebral anomalies by a second or third trimester ultrasound screening between January 2020 and April 2024 at a single center were included in the study. Chromosome microarray analysis (CMA) as a first-line diagnostic test was performed. Whole exome sequencing (WES) was further applied to the cases with negative CMA results. Results A total of 12 fetuses presenting vertebral defects were included. Isolated and non-isolated vertebral malformations were reported for eight (66.7%, 8/12) and four (33.3%, 4/12) fetuses, respectively. Congenital heart defects, microphthalmia, and duplicated kidney were among other structural anomalies associated with vertebral malformation in non-isolated cases. Of the 12 fetuses, five (41.7%) had positive results for prenatal diagnosis. CMA detected de novo 16p11.2 deletions (including the TBX6 gene) in three fetuses and a 7q36.1-q36.3 deletion in one fetus, respectively. WES followed by Sanger sequencing validation identified a novel frameshift duplication mutation TBX6 NM_004608.4: c.989_990dup p.(G331Pfs*168) in trans with the hypomorphic T-C-A haplotype (defined by SNPs rs2289292, rs3809624, and rs3809627) on the opposite allele in a fetus with a negative result for pathogenic copy number variants. There was no statistically significant difference in diagnostic yield between the isolated (25.0%, 2/8) and non-isolated (75%, 3/4) cases (Fisher exact test, P  = 0.141). In all cases, six (50%, 6/12) had termination of pregnancy, three (25%, 3/12) had live birth with normal development at the latest follow-up, and three declined or were lost to follow-up. All live births were from cases with negative CMA and WES results. Conclusion CMA has a good performance for the diagnosis of fetuses presenting vertebral defects, and WES can further improve the diagnostic yield from the cases with negative CMA results. More studies are needed to reveal the etiologies and enhance the prenatal management of fetal vertebral defects.

Background The short arm of chromosome 16 is highly susceptible to homologous recombination through nonallelic genes. This results in microdeletions/microduplications that can lead to neurodevelopmental disorders. However, incomplete penetrance and phenotypic diversity after birth exacerbate the uncertainty in prenatal genetic counseling. Methods A total of 24,000 cases with prenatal diagnoses were retrospectively analyzed. Chromosome microarray analysis (CMA) was performed on 17,000 cases, of which 81 (0.48%) had chromosome 16 short‐arm microdeletions/microduplications. Results Of the 81 fetuses with chromosome 16 short‐arm microdeletions/microduplications, 36 and 28 had 16p11.2 and 16p13.11 microdeletions/microduplications, respectively. Ten, four, and three fetuses had 16p12.2, 16p13.12p13.11, and 16p13.12p1.3 microdeletions, respectively. Among the 36 fetuses with 16p11.2 microdeletions/microduplications, 33 had abnormal intrauterine ultrasound phenotypes, the most common being skeletal system abnormalities. Among the 28 fetuses with 16p13.11 microdeletions/microduplications, 19 had abnormal intrauterine ultrasound phenotypes, including 15 with abnormal ultrasonic soft markers. Among the 10 fetuses with the 16p12.2 microdeletions, six had abnormal ultrasound findings, and four had skeletal system abnormalities. After genetic counseling, 44 patients were selected and tested for family verification, of which 22 were de novo, while 22 were inherited from phenotypically normal parents. Among the 47 live births, 39 had no abnormalities. Conclusion All fetuses with the 16p13.11 microdeletions/microduplications, and 16p12.2, 16p13.12p13.11, and 16p13.12p1.3 microdeletions were healthy after birth. Hence, chromosome 16 short‐arm microdeletions/microduplications should not be the sole basis for abandoning pregnancy, and clinicians should consider prenatal diagnostic data to maximize diagnostic accuracy. Extent and size of the detected 16p11.2 microdeletion/microduplication.

Background:Chromosomal abnormalities constitute the predominant genetic etiology of early pregnancy loss; however, conventional karyotyping analysis fails to detect submicroscopic genomic imbalances or regions of homozygosity (ROH). This retrospective cohort study utilizes chromosomal microarray analysis (CMA) to systematically investigate chromosomal abnormalities associated with early pregnancy loss.Methods:A cohort of 1006 specimens from products of conception (POCs) was collected and subjected to DNA extraction and CMA. Relevant clinical records were also reviewed.Results:Among the 1006 cases, CMA identified chromosomal abnormalities in a total of 596 cases (59.24%, 596/1006), including 529 cases (52.58%, 529/1006) with chromosomal numerical abnormalities, 58 cases (5.77%, 58/1006) with genomic imbalance, and 9 cases (0.89%, 9/1006) with ROH. The univariable analysis demonstrated that maternal age ≥35 years, paternal age ≥35 years, pregnancy loss at 8–9 weeks, and a history of live birth were significantly associated with an increased risk of numerical chromosomal abnormalities in pregnancy loss. A history of more than two pregnancy losses, pregnancy loss after 10 weeks, and conception via in vitro fertilization-embryo transfer (IVF-ET) were associated with a reduced risk of numerical chromosomal abnormalities. Multivariable regression analyses demonstrated that paternal age ≥35 years and history of live birth did not show a significant correlation. Euploid pregnancies with pathogenic or likely pathogenic copy number variations (CNVs) were not correlated with maternal or paternal age, pregnancy loss history, gestational age, IVF-ET conception, or live birth history.Conclusions:Numerical chromosomal abnormalities are the leading cause of early pregnancy loss, demonstrating significant associations with maternal age, pregnancy loss history, and gestational age. Furthermore, pathogenic or likely pathogenic genomic imbalances may contribute to euploid pregnancy loss, although the incidence of CNVs does not correlate with clinical characteristics. The potential impact of ROH on pregnancy loss warrants further investigation.

Objective This study aims to perform a prenatal genetic diagnosis of a high-risk fetus with trisomy 7 identified by noninvasive prenatal testing (NIPT) and to evaluate the efficacy of different genetic testing techniques for prenatal diagnosis of trisomy mosaicism. Methods For prenatal diagnosis of a pregnant woman with a high risk of trisomy 7 suggested by NIPT, karyotyping and chromosomal microarray analysis (CMA) were performed on an amniotic fluid sample. Low-depth whole-genome copy number variation sequencing (CNV-seq) and fluorescence in situ hybridization (FISH) were used to clarify the results further. In addition, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was performed to analyze the possibility of uniparental disomy(UPD). Results Amniotic fluid karyotype analysis revealed a 46, XX result. Approximately 20% mosaic trisomy 7 was detected according to the CMA result. About 16% and 4% of mosaicism was detected by CNV-seq and FISH, respectively. MS-MLPA showed no methylation abnormalities. The fetal ultrasound did not show any detectable abnormalities except for mild intrauterine growth retardation seen at 39 weeks of gestation. After receiving genetic counseling, the expectant mother decided to continue the pregnancy, and follow-up within three months of delivery was normal. Conclusion In high-risk NIPT diagnosis, a combination of cytogenetic and molecular genetic techniques proves fruitful in detecting low-level mosaicism. Furthermore, the exclusion of UPD on chromosome 7 remains crucial when NIPT indicates a positive prenatal diagnosis of trisomy 7.