Common Chromosomal Abnormality Research Articles

Analysis of copy number variants detected by sequencing in spontaneous abortion.

The incidence of spontaneous abortion (SA), which affects approximately 15-20% of pregnancies, is the most common complication of early pregnancy. Pathogenic copy number variations (CNVs) are recognized as potential genetic causes of SA. However, CNVs of variants of uncertain significance (VOUS) have been identified in products of conceptions (POCs), and their correlation with SA remains uncertain. Of 189 spontaneous abortion cases, trisomy 16 was the most common numerical chromosome abnormality, followed by monosomy X. CNVs most often occurred on chromosomes 4 and 8. Gene Ontology and signaling pathway analysis revealed significant enrichment of genes related to nervous system development, transmembrane transport, cell adhesion, and structural components of chromatin. Furthermore, genes within the VOUS CNVs were screened by integrating human placental expression profiles, PhyloP scores, and Residual Variance Intolerance Score (RVIS) percentiles to identify potential candidate genes associated with spontaneous abortion. Fourteen potential candidate genes (LZTR1, TSHZ1, AMIGO2, H1-4, H2BC4, H2AC7, H3C8, H4C3, H3C6, PHKG2, PRR14, RNF40, SRCAP, ZNF629) were identified. Variations in LZTR1, TSHZ1, and H4C3 may contribute to embryonic lethality. CNV sequencing (CNV-seq) analysis is an effective technique for detecting chromosomal abnormalities in POCs and identifying potential candidate genes for SA.

Turner syndrome with isochromosome Xq as a cause of granulomatous hepatitis: a case report

Introduction: Turner syndrome (TS) is the most common sex chromosome abnormality in women, caused by a complete or partial absence of the second sex chromosome. The karyotype 46, X,i(Xq) is the underlying cause in about 10% of the cases of TS. Hepatic abnormalities are frequent in Turner syndrome. Granulomas are relatively common in liver samples but are very rarely reported in Turner syndrome. Case Presentation: a 15-year-old female with Turner syndrome attended a consultation for evaluation of elevated liver enzymes. Her chromosomal analysis showed mosaicism 46, X (iso xq)100%. There were no stigmata of chronic liver disease. A liver biopsy showed granulomatous hepatitis. Other causes of hepatic granulomas have been excluded. Ursodeoxycholic Acid (UDCA) therapy leads to the normalization of transaminases. Clinical Discussion: Although Hepatic involvement is common and mostly asymptomatic in Turner syndrome, the mechanism of liver injury is not well understood. The hepatic histological changes in these cases are variable and range from minimal abnormalities to nonalcoholic steatohepatitis (NASH), liver architectural changes, and biliary lesions. Hepatic granulomas are associated with a wide range of systemic disorders but are very rarely reported in tuner syndrome. Normalization of liver enzymes after treatment with Ursodeoxycholic Acid (UDCA) was previously reported, but the importance of this approach is to be determined. Conclusion: Granulomatous hepatitis may be associated with Turner syndrome and may be added to the histological patterns encountered in this disorder.

INVESTIGATING THE LANGUAGE DEVELOPMENT OF INDIVIDUALS WITH DOWN SYNDROME, AND HIGHLIGHTING THE IMPORTANCE OF SPEECH THERAPY

Down syndrome is the most common viable numerical chromosomal abnormality, affecting one in every 600 births. It is the most common cause of intellectual disability due to genetic factors. Nearly all individuals with this syndrome have an extra copy of the 21st, leading to cognitive and physical disabilities. Down syndrome can be detected through prenatal screening and is classified into three categories: trisomy 21, mosaicism, and translocation. The main aim of this study is to investigate the linguistic characteristics of people with Down syndrome and demonstrate the value of speech therapy. Statistical analysis shows that the linguistic development of individuals with Down syndrome differs in every subsection from normal development. There are deficiencies not only in their linguistic development (i.e., phonology, morphology, syntax, and pragmatics) but also in many cognitive categories (e.g., memory). Furthermore, this study confirmed the value of speech therapy through personalized intervention. However, we found that the speech therapists who participated in this survey did not have the appropriate expertise. Their knowledge of Down syndrome was good, but they needed a deeper understanding of the syndrome.<p> </p><p><strong> Article visualizations:</strong></p><p><img src="/-counters-/edu/0748/a.php" alt="Hit counter" /></p>

Genetic evaluation using next-generation sequencing of children with short stature: a single tertiary-center experience.

We used next-generation sequencing (NGS) to investigate the genetic causes of suspected genetic short stature in 37 patients, and we describe their phenotypes and various genetic spectra. We reviewed the medical records of 50 patients who underwent genetic testing using NGS for suspected genetic short stature from June 2019 to December 2022. Patients with short stature caused by nongenetic factors or common chromosomal abnormalities were excluded. Thirty-seven patients from 35 families were enrolled in this study. We administered one of three genetic tests (2 targeted panel tests or whole exome sequencing) to patients according to their phenotypes. Clinical and molecular diagnoses were confirmed in 15 of the 37 patients, for an overall diagnostic yield of 40.5%. Fifteen pathogenic/likely pathogenic variants were identified in 13 genes (ACAN, ANKRD11, ARID1B, CEP152, COL10A1, COL1A2, EXT1, FGFR3, NIPBL, NRAS, PTPN11, SHOX, SLC16A2). The diagnostic rate was highest in patients who were small for their gestational age (7 of 11, 63.6%). Genetic evaluation using NGS can be helpful in patients with suspected genetic short stature who have clinical and genetic heterogeneity. Further studies are needed to develop patient selection algorithms and panels containing growth-related genes.

The Jacobs Syndrome: Clinical Case

This work describes a clinical case of a violation of sex formation in a newborn child with Y-chromosome dysomy. The diagnostic challenges related to Y-chromosome variability and associated anomalies in sex development are being considered. The work presents clinical and laboratory data for Y-chromosome dysomy. It is noted that the challenge in diagnosing disorders of sex development is associated with the polymorphic clinical manifestations of this syndrome. It is noted that the presence of Y-chromosome dysomy is one of the most common chromosomal abnormalities, ranking third after Down syndrome and Klinefelter syndrome. It is often found that this pathology results in anomalies in genital development. A Y-chromosome polysomy is associated with variable phenotypic manifestations in gonadal development disorders.

Recurrent Respiratory Infections in Children with Down Syndrome: A Review.

Down Syndrome (DS) is the most common chromosomal abnormality compatible with life. The life of patients suffering from DS can be strongly impacted by Recurrent Respiratory tract Infections (RRIs), leading to an increased rate of hospitalisation, a higher need for intensive care and fatality. With a literature review, we summarise here the main etiological factors for RRI in this category of patients, particularly focusing on airway malformations such as tracheomalacia, tracheal bronchus and bronchomalacia, comorbidities associated with the syndrome, like congenital heart diseases, dysphagia, gastroesophageal reflux, musculoskeletal involvement and obesity, and immunologic impairments, involving both innate and adaptive immunity. For these patients, a multidisciplinary approach is imperative as well as some preventive strategies, in particular vaccinations in accordance with their national schedule for immunization.

Ultrasound signs of fetal chromosomal abnormalities at 11–14 weeks of pregnancy and its value in the era of modern genetic testing

A steady increase in average maternity age at the time of first childbirth lead to a higher risk of fetal chromosomal abnormalities. The Order No. 1130n of the Ministry of Health of the Russian Federation establish the screening protocol at 11–14 weeks of gestation with assessing the followed criteria of fetal chromosomal pathology: the nuchal translucency thickness, nasal bone measurement, ductus venosus pulsatility index, tricuspid regurgitation, and heart rate. The value of non-invasive prenatal testing (NIPT) in the early prenatal diagnosis of the most common chromosomal abnormalities, as the trisomies 21, 18, 13, and monosomy X is also increasing. Additionally, numerous other fetal karyotype abnormalities can also be suspected at 11–14 weeks of gestation by revealing a number of other ultrasound signs. The article presents the literature review on additional ultrasound signs of various, both more and less common, chromosomal abnormalities. Pathological signs, abnormalities of fetal anatomy and extrafetal structures in the first trimester, which could be used as additional ultrasound signs of chromosomal pathology of various organs and systems (central nervous system and head, heart and blood vessels, urinary system, abdominal organs, fetal skeleton, as well as the placenta, umbilical cord, amniotic membranes) are described in the article. Despite the use of NIPT, including its extended panels, there remains a need to use ultrasound to detect the signs of rarer, but no less significant chromosomal pathologies, such as triploidies, mosaic trisomies, rare autosomal trisomies, duplications, and deletions.

DNA Sequencing of CD138 Cell Population Reveals TP53 and RAS-MAPK Mutations in Multiple Myeloma at Diagnosis.

Multiple myeloma is a hematologic neoplasm caused by abnormal proliferation of plasma cells. Sequencing studies suggest that plasma cell disorders are caused by both cytogenetic abnormalities and oncogene mutations. Therefore, it is necessary to detect molecular abnormalities to improve the diagnosis and management of MM. The main purpose of this study is to determine whether NGS, in addition to cytogenetics, can influence risk stratification and management. Additionally, we aim to establish whether mutational analysis of the CD138 cell population is a suitable option for the characterization of MM compared to the bulk population. Following the separation of the plasma cells harvested from 35 patients newly diagnosed with MM, we performed a FISH analysis to detect the most common chromosomal abnormalities. Consecutively, we used NGS to evaluate NRAS, KRAS, BRAF, and TP53 mutations in plasma cell populations and in bone marrow samples. NGS data showed that sequencing CD138 cells provides a more sensitive approach. We identified several variants in BRAF, KRAS, and TP53 that were not previously associated with MM. Considering that the presence of somatic mutations could influence risk stratification and therapeutic approaches of patients with MM, sensitive detection of these mutations at diagnosis is essential for optimal management of MM.

The detailed profile of congenital heart diseases in 254 children with Down syndrome in Saudi Arabia

BackgroundDown syndrome is the most common chromosomal abnormality in humans. It is associated with several congenital anomalies, including a spectrum of congenital heart diseases. Understanding the true prevalence and distribution of congenital heart diseases is essential for health resource planning, outcomes, and family counseling.This study aimed to assess the prevalence and distribution of congenital heart disease in children with Down syndrome. It is a retrospective cohort review that included all patients treated at King Abdulaziz University Hospital. Frequencies were estimated using the SPSS software and comparisons were made using Student’s t test.ResultsThe ages of the 254 subjects ranged from less than 1 year to 53 years. Of these, 44.5% were female and 40.6% were Saudi nationals. Congenital heart disease was present in 66.5% with a significant difference between Saudi nationals 44.6%) and non-Saudi nationals 71.5% (P = 0.01). The atrioventricular septal defect was the most common pathology, representing 33.1% of all congenital heart diseases followed by perimembranous ventricular septal defect 18.9%, and right ventricular pathology 10.2%.ConclusionThe prevalence of congenital heart diseases in Saudi children with Down Syndrome is similar to that reported worldwide. Septal defects and right-sided pathologies are the dominant forms of congenital heart diseases, with atrioventricular septal defect and perimembranous ventricular septal defect representing the most common pathologies.

Effects of Hormone Replacement Therapy on Bone Mineral Density in Korean Adults With Turner Syndrome.

Turner syndrome (TS) is a common chromosomal abnormality, which is caused by loss of all or part of one X chromosome. Hormone replacement therapy in TS is important in terms of puberty, growth and prevention of osteoporosis however, such a study has never been conducted in Korea. Therefore, the purpose of our study was to determine relationship between the starting age, duration of estrogen replacement therapy (ERT) in TS and develop a hormone replacement protocol suitable for the situation in Korea. This is retrospective study analyzed the medical records in TS patients treated at the Severance hospital, Yonsei University College of Medicine, Seoul, Korea from 1997 to 2019. Total of 188 subjects who had received a bone density test at least once were included in the study. Korean National Health and Nutrition Examination Survey (KNHANES) was used for achieving bone mineral density (BMD) of normal control group. Student's t-test, Mann-Whitney U test, ANOVA and correlation analysis were performed using SPSS 18.0. Each BMD measurement was significantly lower in women with TS than in healthy Korean women. Early start and longer duration of ERT is associated with higher lumbar spine BMD but not femur neck BMD. Femur neck BMD, but not lumbar spine BMD was significantly higher in women with mosaicism than 45XO group. Early onset and appropriate duration of hormone replacement therapy is important for increasing bone mineral density in patients with Turner syndrome. Also, ERT affects differently to TS patients according to mosaicism.

Knowledge and attitude of Down syndrome and prenatal screening among women in Hail, Saudi Arabia

Background and Aims: Down syndrome is the most common chromosomal abnormality occurring in live born infants. In Saudi Arabia termination of pregnancy is considered illegal and both religiously and culturally unacceptable. Our aim was to explore views, attitudes, and knowledge about Down syndrome, prenatal screening, integrating Down syndrome individuals in the community, willingness to terminate preg¬nancy. Methods: This cross-sectional study was conducted using a pre-validated questionnaire and carried out through face-to-face interviews, in Hail, Saudi Arabia from July-August 2019. Results: A total of 337 married women participated in this study, about Half were college graduates 157\\337(46.6%). Participants expressed opposition as “extremely opposed” to Down syndrome individuals to be involved in the community in schools, have jobs and attend public places 108\\337 (32.0%), 140\\337(41.5%) and 139\\337(41.2%) respectively. Illiterate participants were more willing to continue a pregnancy with Down syndrome fetus (AOR 9.7,95%CI: 2.2 – 42.8, p=0.003). In comparison, participants with college education were more willing to terminate (OR 1.6 95% CI: 1.0- 2.4, P=0.038). Moreover, awareness about prenatal tests were of no significant association with the willingness to terminate. Conclusions: This study has shown lack of knowledge about Down syndrome and most Saudi women in Hail are willing to undergo NIPT to prepare mentally for the child, but not go as far as TOP. This study also highlights the opinions of women towards the integration of DS individuals in the community. Further research on these questions would be useful to explore the reasons for the stigma surrounding the inclusion of DS individuals.

Detection of pathogenic variants related to severe dominant monogenic diseases by non-invasive prenatal testing (NIPT-SGD)

Non-invasive prenatal testing (NIPT) as a screening method for common chromosomal abnormalities such as trisomy 21, 18, and 13 has been widely adopted. In the last five years, the possibility of NIPT to detect common single-gene disorders (SGD) due to de novo mutations or paternal inherited had been reported worldwide. Our report describes the first cases in Vietnam that identified pathogenic/likely pathogenic variants by NIPT-SGD in fetuses. These findings were compared with the diagnostic testing (whole exome sequencing/WES) on amniotic fluid/placenta tissue/umbilical cord blood samples. Single-gene NIPT detected pathogenic variants in the fetuses on TSC2, FGFR3, FGFR2 (two cases), and PTPN11 genes. All results coincided with the subsequent diagnosis. Preliminary research showed the potential of cell-free fetal DNA analysis for prenatal screening of dominant single-gene mutations.

Incidence, distribution, disease spectrum, and genetic deficits of congenital heart defects in China: implementation of prenatal ultrasound screening identified 18,171 affected fetuses from 2,452,249 pregnancies

BackgroundCongenital heart defects (CHDs) are the most common birth defects. Assessment of the incidence, distribution, disease spectrum, and genetic deficits of fetal CHDs in China is urgently needed.MethodsA national echocardiography screening program for fetal CHDs was implemented in 92 prenatal screening–diagnostic centers in China.FindingsA total of 18,171 fetal CHD cases were identified from 2,452,249 pregnancies, resulting in 7·4/1,000 as the national incidence rate of fetal CHD. The incidences of fetal CHD in the six geographical regions, the southern, central, eastern, southwestern, northern, and northwestern, were 7·647 (CI: 7·383–7·915), 7·839 (CI: 7·680–8·000), 7·647 (CI: 7·383–7·915), 7·562 (CI: 7·225–7·907), 5·618 (CI: 5·337–5·906), and 4·716 (CI: 4·341–5·108), respectively, per 1,000 pregnancies. Overall, ventricular septal defect was the most common fetal CHD, accounting for 17.04% of screened pregnancies nationwide, and tetralogy of Fallot, the most common anomaly in the major defect of fetal CHD, was the second most common, accounting for 9.72%. A total of 76.24% cases of fetal CHD were found to be an isolated intracardiac single defect. The remaining 23.76% of cases of fetal CHD had multiple heart defects. Among all extracardiac malformations, the central nervous system (CNS) was the most common tissue with extracardiac anomalies associated with CHD, accounting for 22.89% of fetal CHD cases. Chromosomal karyotyping identified trisomy 18 as the most common chromosomal abnormality in fetal CHD. We also documented that CHD-containing syndromes could be identified with a comprehensive approach integrating prenatal ultrasound, MRI, pathological autopsy, and cytogenetics and molecular genetics.ConclusionImplementation of prenatal echocardiography as a practically feasible platform to screen fetal CHD will reduce the financial and emotional burden of CHD, which may facilitate intrauterine and neonatal intervention of CHD.

The prevalence and spectrum of thyroid dysfunction among children with Down syndrome attending the paediatric services at two tertiary hospitals in Pretoria, South Africa

Background. Down syndrome (DS) is the most common chromosomal abnormality in the paediatric setting, and thyroid dysfunction is more commonly encountered in this population than among the general population. The literature shows that the most common type of thyroid dysfunction seen in these children is subclinical hypothyroidism.Objective. The purpose of this study was to establish the prevalence and spectrum of thyroid disease in this population with the aim of establishing easy-to-follow protocols. Method. A retrospective study was conducted in children with DS who were seen at the paediatric genetic clinic at two academic hospitals. Data were collected from the hospital files and the results were extracted from the National Health Laboratory Service database system. Results. A total of 158 children were recruited; 25 children were excluded as they had had no thyroid function tests done. From the total of 133 included children, 70 (52.6%) were male. Babies born in one of the two hospitals numbered 60 (45.1%), whereas 54.9% were born in the other hospital. A total of 77 (57.9%) were found to have thyroid dysfunction; 55.8% of these patients were male. The most common thyroid abnormality was subclinical hypothyroidism in n=66/133 (49.6%), accounting for 85.7% of the causes of the thyroid dysfunction. Most children (n=45/133 (33.8%)) had their first thyroid function test done before the age of 2 months, followed by the age group of 1 - 5 years (n=34/133 (25.56%)). The total number of children started on treatment for their thyroid dysfunction was n=5/77 (6.49%). Conclusion. Thyroid dysfunction is seen more commonly in children with DS compared with the general population, which was very evident in the present study. A standardised protocol will have a significant impact on the early management of these children, to prevent further cognitive impairment, especially in developing countries and at any level of healthcare. The recommendations for thyroid dysfunction screening by the American Academy of Pediatrics can be adjusted and tailored for the South African population. Early diagnosis and referral of children with DS to a secondary- or tertiary-level facility is of utmost benefit for these children for screening and treatment of comorbidities and complications.

Cytogenetics and Molecular Diagnosis in Horse Infertility

As the popularity of horse breeding stays steady, many breeders and owners send their horses samples to cytogenetics analysis for signs of infertility or other genetic abnormalities. Here, we report three cases of horses that were subjected to chromosome analysis due to infertility issues. Unfortunately, in the case of the H304 mare, the horse has a normal 64, XX female karyotype and no chromosomal abnormality was observed to explain the infertile issue. In the case of the H305 mare, the horse has a 64, XY male karyotype which indicates genetically male and no sign of chromosomal abnormality under cytogenetic analysis. However, PCR analysis indicates the loss of the SRY in the Y chromosome. This is a typical male to female sex reversal and one of the most common genetic sex abnormalities in horses. In the H306 mare, the horse has only one X chromosome; 63, XO, called X monosomy. This is the most common sex chromosomal abnormality in horses. The combination of clinical cytogenetic analysis and the use of PCR are the strongest tool to determine the chromosomal abnormality in the equine industry and the case H305 is a good example to support how these two different approaches compensate each other to generate a reliable diagnosis. Determination of genetic abnormalities using two techniques will help horse breeders and equine practitioners to make the most informed decisions about breeding plans.

The Use of Targeted RNA- Sequencing Assay in the Diagnostic Evaluation of Acute Myeloid Leukaemia(AML)

Background: Acute Myeloid Leukaemia (AML) is a clinically heterogenous disease characterised by chromosomal and genetic abnormalities which guide risk stratification and management. Hence timely cytogenetic and molecular profiling is essential to initiate appropriate treatment. Approximately 30% of AML cases have fusion genes. We use a combination of fluorescence in situ hybridization (FISH) and the Acute Leukaemia Diagnostic Panel Real-Time PCR assay and targeted RNA-sequencing (Archer Fusion Plex Pan-Heme panel) to rapidly screen for common chromosomal abnormalities and fusion genes. The Fusion Plex Pan-Heme panel is an Anchored Multiplex PCR (AMP™)-based next-generation sequencing (NGS) product to detect and identify fusions, point mutations and expression levels from ribonucleic acid (RNA) input. Both known and novel fusions can be identified. The Acute Leukaemia Diagnostic Panel (TruPCR Acute Leukaemia Diagnostic Panel) is a real time PCR assay that detects 14 fusion genes with 28+ breakpoints commonly associated with AML and ALL, and variants in 5 genes associated with AML. Aims: To evaluate the RNA-sequencing Kit to detect rearrangements, gene fusions on bone marrow specimens from newly diagnosed AML patients; and compare concordance of targeted RNA-sequencing, FISH and qPCR in identifying leukaemia fusion genes. Methods: We retrospectively reviewed FISH, qPCR and targeted RNA-sequencing data for new AML cases diagnosed in the specialist integrated haematological malignancy diagnostic service (SIHMDS) at University College London Hospital over a one year period: 01 January 2022 to 31 December 2022. Results: 87 cases were included. They are classified based on ELN Cytogenetic Risk Group and types of AML as per Table 1. 28 (31%) of 87 patients had a detectable fusion gene by targeted RNA-sequencing (Figure 1). 22/28 were detected by targeted RNA-sequencing, FISH and qPCR. The 6/28 fusion genes detected by targeted RNA-sequencing, but not by FISH /qPCR were: - TFG-ADGRG7 (n=1) - NUP98-NSD1 (n=1) - JAK2-ETV6 (n=1) - LMO1-RIC3(n=1) - SSBP2-CHD1 (n=1)-clinical significance not known - CBFB-MYH11 (n=1) rare breakpoint - detected by FISH, not by PCR The discordant results were due to unavailability of probes/genes in FISH and qPCR panels. Summary/Conclusion: The ability to risk-stratify newly diagnosed AML patients allows earlier initiation of targeted therapies. We found that targeted RNA-sequencing (Archer Fusion Plex) is sensitive and showed 100% concordance in identifying fusions associated with good cytogenetic risk AML. Targeted RNA-sequencing can also identify high risk fusion genes such as NUP98-NSD1 for which FISH fusion probes are not routinely used. These may have been otherwise undetected, but can subsequently be confirmed by RT-PCR and importantly allow the generation of molecular measurable residual disease (MRD) assays to assess treatment response. We conclude that targeted RNA-sequencing can be implemented in a diagnostic laboratory to complement FISH-analysis for the detection of recurrent and rare gene fusions in AML diagnosis.

OGM and WES identifies translocation breakpoints in PKD1 gene in an polycystic kidney patient and healthy baby delivered using PGT

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is one of the most common autosomal dominant genetic diseases. Whole exome sequencing (WES) is a routine tool for diagnostic confirmation of genetic diseases, and it is usually performed to confirm the clinical diagnosis in ADPKD. Reciprocal translocation is the most common chromosomal structural abnormalities and most of its carriers have normal phenotypes until they are encountered infertility problems in adulthood. However, for the polycystic kidney disease caused by abnormal chromosome structure, WES is difficult to achieve the purpose of gene diagnosis.MethodsADPKD-related genes were detected by WES; Chromosomal karyotyping and Optical Genome Mapping (OGM) were used to detect structural variant; The genomic break-point locations and the abnormal splicing were detected by reverse transcription-PCR and Sanger sequencing; The karyomapping gene chip and Next-Generation Sequencing (NGS) were performed to screen aneuploidy and to distinguish the non-carrier embryos from the carrier embryos.ResultsNo pathogenic variant was found after the first round of WES analysis. Karyotyping data showed 46, XX, t (16; 17) (p13.3; q21.3). With the help of OGM, the translocation breakpoint on chromosome 16 was located within the PKD1 gene. With re-analysis of WES raw data, the breakpoint of translocation was verified to be located at the c.10618 + 3 of PKD1 gene. Based on this molecular diagnosis, a non-carrier embryo was selected out from three blastocysts. With preimplantation genetic testing (PGT) after in vitro fertilization (IVF), it was then transferred into uterus. With confirmation by prenatal and postnatal testing, the pedigree delivered a healthy baby.ConclusionWe identified a case of ADPKD caused by balanced translocation and assisted the patient to have a healthy child. When the phenotype was closely related with a monogenic disease and the WES analysis was negative, chromosomal structural analysis would be recommended for further genetic diagnosis. Based on the precision diagnosis, preventing the recurrence of hereditary diseases in offspring would be reachable.

A Retrospective Analysis of Robertsonian Translocations from a Single Center in China

Robertsonian translocations (ROBs) are the most common structural chromosomal abnormalities in the general population, with an estimated incidence rate of 1/1000 births. In this study, we retrospectively analyzed the cases of ROBs from September 2015 to August 2022 and totally identified ROB carriers from 84,569 specimens karyotyped in a single accredited laboratory in China, including 189 cases of balanced ROBs and 3 of mosaic ROBs. Microsoft Excel and descriptive statistics were used to record and analyze the collected data. The male/female ratio of ROBs is 1/1.29, with der(13;14) and der(14;21) being the main karyotypes. Among the 192 patients, 7 were lost to follow-up, 82 had given birth, and 103 were childless (such as miscarriage, fetal chromosomal abnormalities, in vitro fertilization (IVF) failure, or divorce). A total of 44 amniocenteses were performed in 42 couples; ROB cases with natural pregnancies showed that the normal karyotype and balanced ROBs of fetal accounted for 66.67% (16/24), while the results of assisted pregnancies showed 90.00% (18/20). This study represents the largest collections of ROBs in Jiangxi population and reminder that the ROB carriers can achieve the ideal outcome for pregnancy with the appropriate genetic guidance and assisted reproductive technologies (ART).

Single-cell RNA sequencing of a new transgenic t(8;21) preleukemia mouse model reveals regulatory networks promoting leukemic transformation.

T(8;21)(q22;q22), which generates the AML1-ETO fusion oncoprotein, is a common chromosomal abnormality in acute myeloid leukemia (AML) patients. Despite having favorable prognosis, 40% of patients will relapse, highlighting the need for innovative models and application of the newest technologies to study t(8;21) leukemogenesis. Currently, available AML1-ETO mouse models have limited utility for studying the pre-leukemic stage because AML1-ETO produces mild hematopoietic phenotypes and no leukemic transformation. Conversely, overexpression of a truncated variant, AML1-ETO9a (AE9a), promotes fully penetrant leukemia and is too potent for studying pre-leukemic changes. To overcome these limitations, we devised a germline-transmitted Rosa26 locus AE9a knock-in mouse model that moderately overexpressed AE9a and developed leukemia with long latency and low penetrance. We observed pre-leukemic alterations in AE9a mice, including skewing of progenitors towards granulocyte/monocyte lineages and replating of stem and progenitor cells. Next, we performed single-cell RNA sequencing to identify specific cell populations that contribute to these pre-leukemic phenotypes. We discovered a subset of common myeloid progenitors that have heightened granulocyte/monocyte bias in AE9a mice. We also observed dysregulation of key hematopoietic transcription factor target gene networks, blocking cellular differentiation. Finally, we identified Sox4 activation as a potential contributor to stem cell self-renewal during the pre-leukemic stage.

Predicting risk of blastocyst aneuploidy among women with previous aneuploid pregnancy loss: a multicenter-data-based multivariable model.

Can blastocyst aneuploidy be predicted for patients with previous aneuploid pregnancy loss (PAPL) and receiving preimplantation genetic testing for aneuploidy (PGT-A)? Multivariable logistic regression models were established to predict high risk of blastocyst aneuploidy using four identified factors, presenting good predictive performance. Aneuploidy is the most common embryonic chromosomal abnormality leading to pregnancy loss. Several studies have demonstrated a higher embryo aneuploidy rate in patients with PAPL, which has suggested that PGT-A should have benefits in PAPL patients intending to improve their pregnancy outcomes. However, recent studies have failed to demonstrate the efficacy of PGT-A for PAPL patients. One possible way to improve the efficacy is to predict the risk of blastocyst aneuploidy risk in order to identify the specific PAPL population who may benefit from PGT-A. We conducted a multicenter retrospective cohort study based on data analysis of 1119 patients receiving PGT-A in three reproductive medical centers of university affiliated teaching hospitals during January 2014 to June 2020. A cohort of 550 patients who had one to three PAPL(s) were included in the PAPL group. In addition, 569 patients with monogenic diseases without pregnancy loss were taken as the non-PAPL group. PGT-A was conducted using single nucleotide polymorphism microarrays and next-generation sequencing. Aneuploidy rates in Day 5 blastocysts of each patient were calculated and high-risk aneuploidy was defined as a rate of ≥50%. Candidate risk factors for high-risk aneuploidy were selected using the Akaike information criterion and were subsequently included in multivariable logistic regression models. Overall predictive accuracy was assessed using the confusion matrix, discrimination by area under the receiver operating characteristic curve (AUC), and calibration by plotting the predicted probabilities versus the observed probabilities. Statistical significance was set at P < 0.05. Blastocyst aneuploidy rates were 30 ± 25% and 21 ± 19% for PAPL and non-PAPL groups, respectively. Maternal age (odds ratio (OR) = 1.31, 95% CI 1.24-1.39, P < 0.001), number of PAPLs (OR = 1.40, 95% CI 1.05-1.86, P = 0.02), estradiol level on the ovulation trigger day (OR = 0.47, 95% CI 0.30-0.73, P < 0.001), and blastocyst formation rate (OR = 0.13, 95% CI 0.03-0.50, P = 0.003) were associated with high-risk of blastocyst aneuploidy. The predictive model based on the above four variables yielded AUCs of 0.80 using the training dataset and 0.83 using the test dataset, with average and maximal discrepancies of 2.89% and 12.76% for the training dataset, and 0.98% and 5.49% for the test dataset, respectively. Our conclusions might not be compatible with those having fewer than four biopsied blastocysts and diminished ovarian reserves, since all of the included patients had four or more biopsied blastocysts and had exhibited good ovarian reserves. The developed predictive model is critical for counseling PAPL patients before PGT-A by considering maternal age, number of PAPLs, estradiol levels on the ovulation trigger day, and the blastocyst formation rate. This prediction model achieves good risk stratification and so may be useful for identifying PAPL patients who may have higher risk of blastocyst aneuploidy and can therefore acquire better pregnancy outcomes by PGT-A. This work was supported by the National Natural Science Foundation of China under Grant (81871159). No competing interest existed in the study. N/A.