Detection Of Chromosomal Abnormalities Research Articles

Prenatal Screening and Diagnosis: Time for a Paradigm Shift.

Recent advances in genetics and imaging have ushered substantial breakthroughs in screening and diagnosis for chromosomal and structural abnormalities. Thus, it is imperative that health care providers caring for pregnant individuals should reexamine established practices in prenatal screening and diagnosis. In the past, screening for chromosomal abnormalities was based almost entirely on Down syndrome. Pregnant individuals aged > 35 years were considered at "high risk" or of "advanced maternal age" based on age alone; however, the advent of tests with high sensitivity for prenatal detection of chromosomal abnormalities should lead to abandoning that concept, at least from the perspective of chromosomal abnormalities. Given that first-trimester and second-trimester screenings will fail to detect between 5 and 20% of Down syndrome, in most situations, noninvasive testing with cell-free DNA should be the first-line screen for Down syndrome. The fact that over 99% of fetuses with Down syndrome will be detected prenatally with cell-free DNA gives other fetal chromosomal and structural abnormalities increasing prominence. Chromosomal microarray analysis (CMA) permits prenatal detection of several clinically important chromosomal aberrations that cannot be detected by karyotype and may exist in structurally normal fetuses with low-risk cell-free DNA screening. As such, CMA should be more readily conducted when invasive testing is performed, regardless of the presence of a structural abnormality. Isolated sonographic "soft markers" have no clinical significance in patients who have normal cell-free DNA screening, can cause unwarranted anxiety and a negative impact on pregnancy, and perhaps it is time to stop discussing them. Detailed first-trimester ultrasound allows early detection of several severe fetal anomalies and, therefore, in settings with adequately trained personnel and resources, should be used more frequently. This opinion traces the evolution of prenatal screening and diagnosis and advocates for a paradigm shift that aligns with recent developments in prenatal screening and diagnostic capabilities. KEY POINTS: · Noninvasive prenatal testing with cell-free DNA should be available to all pregnant individuals.. · Chromosomal microarray should be available to all pregnant individuals undergoing amniocentesis.. · Patients >35 years with low-risk screening are not at "high risk" for chromosomal abnormalities..

Non-invasive prenatal test identifies circulating cell-free DNA chromosomal abnormalities derived from clonal hematopoiesis in aggressive hematological malignancies

Liquid biopsy is a minimally invasive diagnostic tool for identification of tumor-related mutations in circulating cell-free DNA (cfDNA). The aim of this study was to investigate feasibility, sensitivity, and specificity of non-invasive prenatal test (NIPT) for identification of chromosomal abnormalities in cfDNA from a total of 77 consecutive patients with non-Hodgkin B-cell lymphomas, Hodgkin lymphoma (HL), or plasma cell dyscrasia. In this case series, half of patients had at least one alteration, more frequently in chromosome 6 (23.1%), chromosome 9 (20.5%), and chromosomes 3 and 18 (16.7%), with losses of chromosome 6 and gains of chromosome 7 negatively impacting on overall survival (OS), with a 5-year OS of 26.9% and a median OS of 14.6 months, respectively (P = 0.0009 and P = 0.0004). Moreover, B-cell lymphomas had the highest NIPT positivity, especially those with aggressive lymphomas, while patients with plasma cell dyscrasia with extramedullary disease had a higher NIPT positivity compared to conventional cytogenetics analysis and a worse outcome. Therefore, we proposed a NIPT-based liquid biopsy a complementary minimally invasive tool for chromosomal abnormality detection in hematological malignancies. However, prospective studies on larger cohorts are needed to validate clinical utility of NIPT-based liquid biopsy in routinely clinical practice.

A rapid PCR-free next-generation sequencing method for comprehensive diagnosis of chromosome disease syndromes in prenatal samples.

The aim of this study is to investigate the application performance of rapid copy number variation sequencing (rCNV-seq) technology for the detection of chromosomal abnormalities during prenatal diagnosis. Samples were collected from 424 pregnant women who were at high-risk for noninvasive prenatal screening in Kunming Maternal and Child Care Hospital from January 2018 to May 2022. rCNV-seq technique was used to detect fetal chromosome abnormalities and compare the results with that of chromosomal karyotype analysis. The Result showed that 330 (77.83%, 330/424) cases indicated chromosomal abnormalities among 424 high-risk pregnant women who underwent rCNV-seq. Moreover, 94 (22.17%, 94/424) cases were discovered to have copy number variations. Among the 330 fetuses with chromosomal abnormalities, common autosomal aneuploidy was observed in 203 cases (47.87%, 203/424) and sex chromosome aneuploidy was observed in 91 cases (21.46%, 91/424). Moreover, the abnormalities in multiple chromosomes were discovered in 33 cases (7.78%, 33/424), and the rare autosomal aneuploidy was observed in 3 cases (0.71%, 3/424). There were 63 fetuses (14.86%, 63/424) with pathogenic CNVs among the 94 fetuses with variable copy numbers. Of the 245 pregnant women who voluntarily selected G-band karyotyping, 1 fetus with copy number variation had normal karyotype results, and the remaining women were consistent with rCNV-seq. Our study revealed that rCNV-seq has higher accuracy in detecting common trisomy and can also detect chromosomal microdeletions or microduplications that cannot be detected by G-banding karyotype analysis. There is no effective treatment for chromosomal diseases, so it is particularly important to prevent chromosomal diseases through genetic counseling and prenatal diagnosis of chromosomal diseases.

From Conception to Revelation: Non-Invasive Prenatal Testing Explored

Prenatal testing plays a crucial role in addressing the inherent unpredictability of genetic disorders that can affect unborn children. Non-Invasive Prenatal Testing (NIPT) has emerged as a groundbreaking tool in the realm of prenatal care, enabling the early detection of chromosomal abnormalities. By examining fetal DNA present in the mother's bloodstream, NIPT has achieved remarkable accuracy rates, surpassing invasive techniques that carry inherent risks. However, with these advancements come ethical considerations. The results of NIPT can significantly influence a mother's decision regarding the continuation or termination of pregnancy. This decision can be further complicated by religious beliefs, which often play a pivotal role in guiding choices related to pregnancy. Moreover, receiving a positive result from NIPT can subject expectant mothers to profound emotional stress, highlighting the need for comprehensive counseling and support services. In addition to these ethical concerns, practical limitations persist. The cost of NIPT remains a substantial barrier for many families, potentially limiting its accessibility. Furthermore, NIPT's accuracy can be influenced by factors such as gestational age, with tests often yielding inconclusive results when fetal fractions are low. Despite these challenges, technological innovations, including microarrays and Next Generation Sequencing (NGS), have bolstered the capabilities of NIPT. These advancements enable a more comprehensive assessment of fetal DNA, enhancing the overall quality of prenatal care. As NIPT continues to evolve and integrate with broader genomic technologies, society must engage in thoughtful reflection on its implications. The potential normalization of pregnancy terminations based on genetic information underscores the importance of ethical and societal discussions surrounding the use of NIPT, with a focus on preserving informed patient choices and ensuring comprehensive support for expectant parents facing difficult decisions.

Application of optical genome mapping technology for the detection of chromosomal structural variations

To assess the value of optical genome mapping (OGM) for the detection of chromosomal structural abnormalities including ring chromosomes, balanced translocations, and insertional translocations. Clinical data of four patients who underwent pre-implantation genetic testing concurrently with OGM and chromosomal microarray analysis at the Center of Reproductive Medicine of the Sixth Affiliated Hospital of Sun Yat-sen University from January to October 2022 due to chromosomal structural abnormalities were selected as the study subjects. Some of the results were verified by multi-color fluorescence in situ hybridization. The OGM has successfully detected a balanced translocation and fine mapped the breakpoints in a patient. Among two patients with insertional translocations, OGM has provided more refined breakpoint locations than karyotyping analysis in a patient who had chromosome 3 inserted into chromosome 6 and determined the direction of the inserted fragment. However, OGM has failed to detect the chromosomal abnormality in a patient with chromosome 8 inserted into the Y chromosome. It has also failed to detect circular signals in a patient with ring chromosome mosaicism. OGM has successfully detected chromosomal structural variations in the four patients and provided assistance for their diagnosis.

Detection of chromosomal abnormalities and monogenic variants in fetal cfDNA for prenatal diagnosis.

Detection of chromosomal abnormalities and monogenic variants in fetal cfDNA for prenatal diagnosis.

OneGene PGT: comprehensive preimplantation genetic testing method utilizing next-generation sequencing.

Preimplantation genetic testing for monogenic disorders (PGT-M) allows early diagnosis in embryos conceived in vitro. PGT-M helps to prevent known genetic disorders in affected families and ensures that pathogenic variants in the male or female partner are not passed on to offspring. The trend in genetic testing of embryos is to provide a comprehensive platform that enables robust and reliable testing for the causal pathogenic variant(s), as well as chromosomal abnormalities that commonly occur in embryos. In this study, we describe PGT protocol that allows direct mutation testing, haplotyping, and aneuploidy screening. Described PGT protocol called OneGene PGT allows direct mutation testing, haplotyping, and aneuploidy screening using next-generation sequencing (NGS). Whole genome amplification product is combined with multiplex PCR used for SNP enrichment. Dedicated bioinformatic tool enables mapping, genotype calling, and haplotyping of informative SNP markers. A commercial software was used for aneuploidy calling. OneGenePGT has been implemented for seven of the most common monogenic disorders, representing approximately 30% of all PGT-M indications at our IVF centre. The technique has been thoroughly validated, focusing on direct pathogenic variant testing, haplotype identification, and chromosome abnormality detection. Validation results show full concordance with Sanger sequencing and karyomapping, which were used as reference methods. OneGene PGT is a comprehensive, robust, and cost-effective method that can be established for any gene of interest. The technique is particularly suitable for common monogenic diseases, which can be performed based on a universal laboratory protocol without the need for set-up or pre-testing.

Deconstructing Preimplantation Genetic Diagnosis

In recent years, infertility rates have been on the rise, with 19% of women aged 15-49 having difficulties getting pregnant and 26% of women having difficulties carrying such fetuses to term (Centers for Disease Control and Prevention, 2019). This statistic also comes in concert with recent research suggesting a rise in congenital defects and abnormalities in neonates (Silesh et al., 2021). In association with these troubling trends, however, are developments in reproductive technologies and assessments. One such of these technologies is preimplantation genetic testing, otherwise abbreviated PGD. This technique uniquely allows for the detection of chromosomal abnormalities and congenital defects and, used in conjunction with IVF treatments, has seen implementation in around 5 percent of all U.S. IVF cycles (“A Microdeletion, They Called It.,” 2015). Despite the hope that the testing method allows for families around the world, PGD is not without its limitations. This paper first explores PGD, determining the testing process and pinpointing its applications' current extent. It then transitions to analyzing the current methods of sampling and analysis housed in PGD, determining their benefits as well as their detriments. It finally contrasts present methods with the many proposed advances, analyzes the feasibility of such advances, and compares the benefits and limitations of these new treatment plans to conclude the best combination of developments is Blastocyst biopsy and Next Generation Sequencing for the advancement of PGD as a diagnostic procedure.

Overview of Noninvasive Prenatal Testing (NIPT) for the Detection of Fetal Chromosome Abnormalities; Differences in Laboratory Methods and Scope of Testing.

Although nearly all noninvasive prenatal testing is currently based on analyzing circulating maternal cell-free DNA, the technical methods usedvary considerably. We review the different methods. Based on validation trials and clinical experience, there are mostly relatively small differences in screening performance for trisomies 21, 18, and 13 in singleton pregnancies. Recent reports show low no-call rates for all methods, diminishing its importance when choosing a laboratory. However, method can be an important consideration for twin pregnancies, screening for sex chromosome abnormalities, microdeletion syndromes, triploidy, molar pregnancies, rare autosomal trisomies, and segmental imbalances, and detecting maternal chromosome abnormalities.

O-288 Implantation, ultrastructure and metabolic profiling of embryos from PGT-M and PGT-A Cycles

Abstract Study question Can metabolic profiling predict embryos at risk of single gene defects and chromosomal abnormalities and how are these reflected in their ultrustructure? Summary answer Different metabolic profiles are observed between embryos with chromosomal abnormalities and monogenic disorders and normal embryos, linked to altered mitochondrial and other organelles’ structure/function What is known already Down’s syndrome embryos and Monosomy 21 embryos have previously been shown to have differential expression of metabolites compared to normal embryos, but limited studies, have investigated in detail the metabolic profiling of embryos with other abnormalities or those with monogenic disorders in comparison to chromosomally normal embryos or their reflection in their ultrustructure. Study design, size, duration 520 embryos were biopsied on day5 for PGT-A (n = 178-47 cycles) or on day3 for PGT-A (n = 178-33 cycles) and PGT-M (n = 164-24 cycles). Following transfer of normal embryos, spare embryos, rejected for transfer following day5 or day3 biopsy were processed for TEM (n = 60 day3 biopsied, n = 60 day5 biopsied/vitrified), 60 unbiopsied/vitrified embryos from egg donation cycles used as control. Culture media were collected from the embryos and analysed by hydrophilic interaction liquid chromatography tandem mass spectrometry (HILIC-MS/MS). Participants/materials, setting, methods PGT-A and PGT-M were performed in 2 IVF Units. Metabolic profiling was conducted in a Forensic Toxicology Laboratory by HILIC-MS/MS (100 metabolites). Ultrastructure analysis by TEM was carried out in an Academic Hospital and Histology/Embryology Laboratory following embryo fixation in 3% glutaraldehyde, 1% osmium tetroxide, washes in PBS and staining with 1% aqueous uranyl acetate. Main results and the role of chance The implantation rates (+ve hCG/ET) for the PGT-M cycles was 68.2% and the for the PGT-A (blastocyst and cleavage biopsy cycles) 64.5% and 65% respectively. Characteristic patient specific metabolic profiles after screening for >100 primary metabolites were observed which differed between normal embryos that had resulted in a viable pregnancy and aneuploid and chaotic embryos although it was more difficult to find clear patterns in embryos with monogenic disorders. Logistic regression analysis revealed a number of metabolites with high predictive value which in combination with embryo score could serve in the future as non-invasive markers for the detection of chromosomal abnormalities before embryo transfer. TEM analysis revealed differences in the quality of cells and organelle activity which were reflected in the embryo metabolic profiles. Abnormal but well developed hatching blastocysts had mainly cells with good mitochondrial morphology/ activity, nice Golgi apparatus and well developed rough and smooth endoplasmic reticulum but depending on the aneuploidy or gene mutation involved, inner cell mass cells with limited organelles and occasionally lipofuscin droplets in the trophectoderm were evident. Chaotic poor quality embryos showed a lower number of mitochondria, often with no cisternae, increased number of vacuoles, and frequently problems in junctions between cells. Limitations, reasons for caution Although metabolic profiles were compared between normal and abnormal embryos, all the normal embryos were transferred to the uterus or remain vitrified for clinical purposes. Therefore the ultrastructure analysis is based only on biopsied abnormal embryos and as control unbiopsied embryos from egg-donation cycles with high chance of being normal. Wider implications of the findings This study shows high implantation rates after PGT—M and PGT-A and identified distinct differences in the metabolic profiles of normal and abnormal embryos providing unique metabolites which in the future could serve as non-invasive biomarkers for the detection of abnormalities before embryo transfer. Trial registration number Not applicable

O-225 May embryonic cfDNA in the culture media play a role as a non-invasive assessment of aneuploidy in PGT

Abstract Non-invasive preimplantation genetic testing for aneuploidies (niPGT-A) in spent blastocyst media (SBM) is a promising technique that has the potential to revolutionize current preimplantation genetic testing procedures. This technique is based in the analysis of the cell-free DNA (cfDNA) released by the embryo during the latest stages of preimplantation development. It allows for the detection of chromosomal abnormalities in embryos without the need for invasive procedures that can harm the embryo (reviewed in Navarro-Sánchez et al., 2022). Our group among others has conducted different studies in this field, and the early clinical application of the cfDNA analysis in the culture medium has been proposed as a screening tool, giving a priority score for embryo transfer based on the media results (Rubio et al., 2019, 2020). In the final analysis of our multicenter study in day-6 and day-7 blastocysts, we have been able to compare the chromosomal results of the SBM with trophectoderm (TE) biopsies in 2,187 samples, and with the inner cell mass ICM in 230 blastocysts. In this study, the analysis of the cfDNA showed a concordance rate of 87% with the ICM biopsy, which is currently considered the gold standard for PGT-A. However, it is important to continue evaluating the factors that may affect the informativity and concordance rates of cfDNA-based assays, such as the culture day when medium is collected, contamination with external and/or cumulus cell DNA, and previous manipulation of the embryos. Multivariate analysis has shown that the longer the time in culture, the higher the informativity rate, and female age had the greatest impact on concordance rates with TE biopsies. Regarding technical aspects, the SBMs with higher number of reads after sequencing resulted in higher concordance rates, reflecting the importance of analysing samples with sufficient DNA quantity. Finally, the predictive value in terms of concordance with TE biopsies was higher for aneuploid blastocyst. No significant independent correlation was observed for embryo quality. The improvements in IVF lab protocols and the use of time-lapse and short incubation protocols for vitrified-thawed blastocysts are also noteworthy, as they may further increase the concordance rates of cfDNA-based assays with blastocysts. In fact, concordance in previously vitrified-thawed blastocysts as result as high as 90%. Regarding clinical outcomes, several groups have evaluated non-invasive PGT-A with transfer of euploid embryos showing good results. In a pilot study with only 7 SETs in couples with PGT-A or PGT-SR indication, 5 pregnancies were achieved resulting in 5 livebirths (Xu et al., 2016). In a second study, in couples with recurrent spontaneous abortion or repeated implantation failure, 50 transfers of euploid media were performed resulting in a 58% clinical pregnancy rate, with 27 healthy babies born (Fang et al., 2019). Similar results were described in good prognosis patients <38 years of age with ongoing pregnancy rates comparable to PGT-A (61.5%), and higher than conventional IVF or ICSI (48.5%) (Franco et al., 2021). Overall, the high concordance rates with trophectoderm biopsies and inner cell mass biopsies are encouraging, and the clinical outcomes with transfer of euploid embryos are promising. It is exciting to see the progress in non-invasive preimplantation genetic testing using cfDNA in culture medium, and it will be interesting to see how this technology evolves and its potential role as a screening or diagnostic tool in the future.

Prenatal detection of chromosomal abnormalities and copy number variants in fetuses with corpus callosum agenesis.

The corpus callosum is the main pathway that connects interhemispheric communication. Agenesis of corpus callosum (ACC) have not consistently detected replicate genetic risk factors, potentially due to Etiological heterogeneity of this trait. This study aimed to retrospectively analyze the molecular basis for the ACC and the potential genotyping-phenotyping association and provide the basis for genetic counselling. Karyotyping and chromosomal microarray analysis were performed for copy number variants. Three cases had 1p36 deletions, two cases had 2q31.2 and 2p16.3 microdeletions, one case had microdeletion of Xq26.3q27.1, five cases involved derived chromosomes due to unbalanced translocations. These cases had variable deletions and duplications with partial overlapping. Phenotypically, besides agenesis of corpus callosum and other brain morphological abnormalities as well as heart abnormalities. ACC may occur alone or be related to other abnormal clinical phenotypes, and its genetic mechanism is very complicated. These results revealed ACC is associated with a variety of chromosomal abnormalities. The findings of the present study expand the genotypes associated with ACC, and further delineation of the genotype-phenotype correlations for ACC. With current applications of chromosome microarray analysis, congenital submicroscopic copy-number variations in fetuses can be detected more effectively.

Trophoblast retrieval from the cervical canal to predict abnormal pregnancy early in gestation: a pilot study

BackgroundThe current detection of fetal chromosomal abnormalities by non-invasive prenatal testing (NIPT) mainly relies on the cell free DNA(cfDNA) in the maternal blood. However, a gestational age of less than 12 weeks or a high maternal BMI affects cfDNA fetal fraction and further the detection by NIPT negatively. In this study, we aim to retrieve the trophoblast cells from the maternal cervix to develop a new sampling method for NIPT enabling an earlier use of NIPT.MethodsWe enrolled three patients who wanted to undergo induced abortion at Beijing Hospital between January 2022 and March 2022. Peripheral blood, cervix specimen, and the abortion tissue were collected and processed for each patient. Allele frequencies of the mutated gene loci of the maternal blood and the cervix sample were compared and the Sex Determining Region Y (SRY) gene was tested.ResultsThe allele frequencies of the mutated gene loci showed no significant difference between the maternal blood and the cervix sample. But we successfully detected signal of the SRY gene in the cervix sample of the only patient carrying a male fetus.ConclusionsThe detection of the SRY gene in a cervix sample indicated a successful retrieval of trophoblast cells from the cervix canal. Further study needs to be conducted to verify our finding before its application to the clinical settings.

Highly Performing Automatic Detection of Structural Chromosomal Abnormalities Using Siamese Architecture

The detection of structural chromosomal abnormalities (SCA) is crucial for diagnosis, prognosis and management of many genetic diseases and cancers. This detection, done by highly qualified medical experts, is tedious and time-consuming. We propose a highly performing and intelligent method to assist cytogeneticists to screen for SCA. Each chromosome is present in two copies that make up a pair of chromosomes. Usually, SCA are present in only one copy of the pair. Convolutional neural networks (CNN) with Siamese architecture are particularly relevant for evaluating similarities between two images, which is why we used this method to detect abnormalities between both chromosomes of a given pair. As a proof-of-concept, we first focused on a deletion occurring on chromosome 5 (del(5q)) observed in hematological malignancies. Using our dataset, we conducted several experiments without and with data augmentation on seven popular CNN models. Overall, performances obtained were very relevant for detecting deletions, particularly with Xception and InceptionResNetV2 models achieving 97.50% and 97.01% of F1-score, respectively. We additionally demonstrated that these models successfully recognized another SCA, inversion inv(3), which is one of the most difficult SCA to detect. The performance improved when the training was applied on inversion inv(3) dataset, achieving 94.82% of F1-score. The technique that we propose in this paper is the first highly performing method based on Siamese architecture that allows the detection of SCA. Our code is publicly available at: https://github.com/MEABECHAR/ChromosomeSiameseAD.

Lung dysplasia in preterm newborn infants: clinical and diagnostic features in the early neonatal period (a clinical case)

The paper presents modern ideas about the clinical and diagnostic features of lung dysplasia in preterm babies in the early neonatal period. Lung dysplasia is shown to be a common and antenatally diagnosed congenital malformation of the respiratory system. The semiotics of lung dysplasia and respiratory distress syndrome in the newborn is compared. The authors consider the characteristics of the main respiratory patterns of traditional and high-frequency oscillatory ventilation, which are often used for respiratory support for premature babies in the neonatal intensive care unit. They discuss the pathogenetic role of hemodynamically significant patent ductus arteriosus in premature babies with respiratory failure. It is emphasized that for the timely detection of chromosomal abnormalities and congenital malformations in a fetus, it is necessary for pregnant and parturient women to regularly attend antenatal care clinics and to undergo prenatal screening. The paper describes a clinical case that considers the capabilities of diagnostic search and the parameters of monitoring the vital functions of a premature baby in the early neonatal period during intensive care in the neonatal intensive care unit.

A de novo PAK1 likely pathogenic variant and a de novo terminal 1q microdeletion in a Chinese girl with global developmental delay, severe intellectual disability, and seizures

BackgroundPathogenic PAK1 variants were described to be causative of neurodevelopmental disorder with macrocephaly, seizures, and speech delay. Herein, we present a de novo PAK1 variant combine with a de novo terminal 1q microdeletion in a Chinese pediatric patient, aiming to provide more insights into the underlying genotype–phenotype relationship.MethodsEnrolled in this study was a 6-year-old girl with clinical features of global developmental delay, severe intellectual disability, speech delay, and seizures from Quanzhou region of China. Karyotype and chromosomal microarray analysis (CMA) were performed to detect chromosome abnormalities in this family. Whole exome sequencing (WES) was performed to investigate additional genetic variants in this family.ResultsNo chromosomal abnormalities were elicited from the entire family by karyotype analysis. Further familial CMA results revealed that the patient had a de novo 2.7-Mb microdeletion (arr[GRCh37] 1q44(246,454,321_249,224,684) × 1]) in 1q44 region, which contains 14 OMIM genes, but did not overlap the reported smallest region of overlap (SRO) responsible for the clinical features in 1q43q44 deletion syndrome. In addition, WES result demonstrated a de novo NM_002576: c.251C > G (p.T84R) variant in PAK1 gene in the patient, which was interpreted as a likely pathogenic variant.ConclusionIn this study, we identify a novel PAK1 variant associated with a terminal 1q microdeletion in a patient with neurodevelopmental disorder. In addition, we believe that the main clinical features may ascribe to the pathogenic variant in PAK1 gene in the patient.

Diagnostic yield of copy number variation sequencing in fetuses with increased nuchal translucency: a retrospective study.

To assess the efficacy of copy number variation sequencing (CNV-seq) and karyotyping for prenatal detection of chromosomal abnormalities in fetuses with increased nuchal translucency. Amniotic fluid samples were extracted from 205 fetuses with increased nuchal translucency (NT ≥ 2.5mm), diagnosed by ultrasound between gestational ages of 11 and 13 + 6weeks. Karyotyping and CNV-seq were performed for detecting chromosomal abnormalities. There are 40 fetuses (19.51%) showing increased NT detected with chromosomal abnormalities in karyotyping, and trisomy 21 was found to be the most common abnormalities. There are 50 fetuses (24.39%) identified with chromosomal abnormalities by CNV-seq. The detection of the applied techniques indicated that CNV-seq revealed higher chromosomal aberrations. The risk of chromosomal abnormalities was significantly increased with NT thickening, from 13.64% in the NT group of 2.5-3.4mm, 38.64% in the NT group of 3.5-4.4mm, and to 51.72% in the NT group of over 4.5mm (P < 0.05). The investigated cases with increased NT with presence of soft markers in ultrasound or high risk in non-invasive prenatal testing presented chromosomal abnormalities in higher rates, comparing with those with isolated NT or low risk (P < 0.05). The results indicated that the risk of chromosomal abnormalities was associated with the NT thickness, detected by karyotype or CNV-seq. The combination application of two analysis was efficient to reveal the possible genetic defects in prenatal diagnosis. The finding suggested that the detection should be considered with ultrasonographic soft markers, and the NT thickness of 2.5-3.4mm could be a critical value for detecting chromosomal abnormalities to prevent the occurrence of missed diagnosis.

Cell-free DNA versus sequential screening for fetal chromosomal abnormalities varied by age: a cost-effectiveness analysis

Cell-free DNA (cfDNA) and sequential screening (SS) are frequently used for prenatal genetic screening. Though cfDNA has higher detection rates for common aneuploidies, SS may better identify risk for other nontargeted aneuploidies. We compared the cost-effectiveness of cfDNA versus SS for detection of fetal chromosome abnormalities across varied age cohorts. A decision-analytic model compared cfDNA versus SS for diagnosis of chromosomal abnormalities across different maternal age cohorts stratified by 5-year increments of < 20, 20-24, 25-29, 30-34, 35-39, 40-44, and >45 years. Chromosomal abnormalities included trisomy 21 (T21), trisomy 18 (T18), trisomy 13 (T13), 45X syndrome, sex chromosome abnormalities (SCA), and other nontargeted chromosomal abnormalities . Probabilities, costs, and utilities were derived from literature and varied in sensitivity analysis. The primary outcome was incremental cost per quality-adjusted life year (QALY). We also considered affected neonates, missed prenatal diagnoses, procedure-related loss (PRL), pregnancy termination (TOP), stillbirth, and neonatal death (NND). The cost-effectiveness threshold was $100,000/QALY. SS was cost-effective for detection of all fetal chromosome abnormalities until age 39. Cell-free DNA was only cost-effective starting at age 40, with an Incremental Cost Effectiveness Ratio (ICER) of $51,919/QALY (40-44 years) and ICER $16,830/QALY ( >44 years). In all maternal age cohorts, cfDNA led to more frequent identification of T21, T18, T13, 45X and SCA but fewer other nontargeted chromosomal abnormalities. cfDNA was associated with more terminations and fewer stillbirths, NND, and PRL. The model was sensitive to the prevalence of T21. When varying the prevalence of T21 in the age 35-39 cohort cfDNA was cost effective when the prevalence of T21 was greater than 0.017 which corresponds with the prevalence of T21 at a maternal age of 39. Compared to cfDNA, SS is a cost-effective screening method for fetal chromosome abnormalities for pregnant persons under the age of 40 at a population-based level.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Feature Fusion Classifier With Dynamic Weights for Abnormality Detection of Amniotic Fluid Cell Chromosome

Chromosomal karyotype is important to determine whether a newborn has a genetic disorder. There are two main categories of chromosomal abnormalities, structural abnormalities in which the chromosome structure is altered, and chromosome number abnormalities. Manual karyotyping is complex and takes a lot of time because it requires a high degree of domain expertise. Based on this investigation proposes a new method of chromosome defect detection based on deep learning with 20,299 chromosome images from Dongguan Kanghua Hospital as data and integrates the diversity of chromosome features, and trains to propose a classifier model based on feature fusion for chromosome abnormality detection. We put forward a feature fusion classifier with dynamic weights (FFCDW) for chromosomal abnormality detection, after data augmentation with three deep learning networks, ResNet, SENet, and VGG19, the three trained models are combined using a dynamic weighting approach. Experiments prove the FFCDW method outperforms these mainstream models of ResNet, SENet, and VGG19. The proposed method based on FFCDW achieves precision of 0.8902 and F1-score of 0.8805 with a small standard deviation (0.00903 and 0.00892, respectively). In addition, the algorithm can automatically assign weights based on the results of a single model, and the strategy with dynamic weights outperforms the strategy with fixed weights in the proposed feature fusion classifier.

Growth plate extracellular matrix defects and short stature in children.

Many etiological factors causing short stature have already been identified in humans. In the last few years, the advent of new techniques for the detection of chromosomal and molecular abnormalities has made it possible to better identify patients with genetic causes of growth failure. Some of these factors directly affect the development and growth of the skeleton, since they damage the epiphyseal growth plate, where linear growth occurs, influencing chondrogenesis. In particular, defects in genes involved in the organization and function of the growth plate are responsible for several well-known conditions with short stature. These genes play a pivotal role in various mechanisms involving the extracellular matrix, intracellular signaling, paracrine signaling, endocrine signaling, and epigenetic regulation. In this review, we will discuss the genes involved in extracellular matrix disorders. The identification of genetic defects in linear growth failure is important for clinicians and researchers in order to improve the care of children affected by growth disorders.