Search

Benign tumors, but rarely cancer, are common in patients with tuberous sclerosis complex (TSC). Blood samples from patients undergoing treatment for TSC at our institution were analyzed for their individual sensitivity to ionizing radiation. Blood samples were collected from 13 adult patients with TSC. The samples were irradiated ex vivo and analyzed by 3-color fluorescence in situ hybridization. In each patient, aberrations were analyzed in 200 metaphases of chromosomes 1, 2, and 4 and scored as breaks. Radiosensitivity was determined by mean breaks per metaphase (B/M) and compared to both healthy donors and oncologic patients. The radiosensitivity (B/M) of the TSC patient cohort (n = 13; female: 46.2%, B/M: 0.48 ± 0.11) was clearly increased compared to healthy individuals of similar age (n = 90; female: 54.4%; B/M: 0.40 ± 0.09; p = 0.001). There was no difference compared to age-matched oncological patients (n = 78; female: 67.9%; B/M 0.49 ± 0.14; p = 0.246). Similarly, the proportion of radiosensitive (B/M > 0.5) and distinctly radiosensitive individuals (B/M > 0.6) was increased in the TSC and oncological patient cohorts (TSC: 30.8% and 7.7%, oncological patients: 46.2% and 14.1%) compared to the healthy individuals (11.1% and 2.2%). Although patients with TSC develop mostly benign and rarely malignant tumors, they are similarly sensitive to radiation as patients with malignant tumors. [ABSTRACT FROM AUTHOR]

Introduction: Myelodysplastic syndrome (MDS) is a heterogeneous disease characterized by cytopenia, marrow dysplasia and has a propensity to develop into acute myeloid leukemia. The disease progression is majorly affected by genetic defects. However, about 40–50% of patients with MDS present with a normal karyotype and develop different courses of disease. Hence, there remains a room to advance the biological understanding and find molecular prognostic markers for cytogenetically normal MDS. Methods: We performed a high-resolution CGH + SNP array along with next-generation sequencing (NGS) of 77 primary diagnosed MDS patients, and also they were clinically followed up. Results: Our study revealed 82 clinically significant genomic lesions (losses/gains) in 49% of MDS patients. CGH + SNP array reduced the proportion of normal karyotype by 30%. SNP array in combination with NGS confirmed the biallelic loss of function of the TP53 gene (2/6), which is a clinically relevant biomarker and new genetic-based MDS entity, i.e., MDS-biTP53, as per the new WHO classification 2022. Genomic region 2p22.3 presented with frequent lesions and also with a more hazard ratio (2.7, 95% CI: 0.37–21) when analyzed by Kaplan-Meier survival analysis. Conclusion: CGH + SNP array changed the cytogenetic and IPSS-R risk group in 18% and 13% of patients, respectively, with an improved prediction of prognosis. This study emphasizes the cytogenetic heterogeneity of MDS and highlights that abnormality with chromosome 2 may have a diagnostic and prognostic impact. Highlights: The study identified 82 different clinically significant CNVs including chromosomal aberrations in MDS. The transcriptome data revealed that CNVs majorly affect genes associated with biological functions such as transcriptions, cell cycle, and immunity. A high frequency of CNVs/loss of heterozygosity was identified at 2p22.3 chromosomal region and found to be associated with disease prognosis. Combination of SNP array with gene mutations successfully established a new genetic-based MDS entity, i.e., MDS-biTP53, in 33.3% of TP53-mutated patients. [ABSTRACT FROM AUTHOR]

Objectives: Our aim was to examine the prenatal profiles of pregnancies affected by an atypical chromosomal aberration, focusing on pathogenic copy‐number variants (pCNVs). We also wanted to quantify the performance of combined first‐trimester screening (cFTS) and a second‐trimester anomaly scan in detecting these aberrations. Finally, we aimed to estimate the consequences of a policy of using non‐invasive prenatal testing (NIPT) rather than invasive testing with chromosomal microarray analysis (CMA) to manage pregnancies identified as high risk by cFTS. Methods: This was a retrospective review of the Danish Fetal Medicine Database of all pregnant women who underwent cFTS and a risk assessment for trisomy 21 between 1 January 2008 and 31 December 2018. Chromosomal aberrations diagnosed prenatally, postnatally or from fetal tissue following pregnancy loss or termination of pregnancy were identified. Chromosomal aberrations were grouped into one of six categories: triploidy; common trisomy (13, 18 or 21); monosomy X; other sex‐chromosome aberration (SCA); pCNV; and rare autosomal trisomy (RAT) or mosaicism. The prevalence of each aberration category was stratified by the individual cFTS markers and trisomy 21 risk estimate, and the size of each pCNV diagnosed by CMA was calculated. Results: We retrieved data on 565 708 pregnancies, of which 3982 (0.70%) were diagnosed with a fetal chromosomal aberration. cFTS identified 87% of the common trisomies, but it also performed well in identifying triploidies (86%), monosomy X (92%), atypical SCAs (58%) and RATs or mosaicisms (70%). pCNVs comprised 27% (n = 1091) of the chromosomal aberrations diagnosed overall, and the prevalence increased during the study period, as prenatal CMA was increasingly being performed. In pregnancies with a maternal age < 30 years, nuchal translucency (NT) thickness ≤ 95th centile, pregnancy‐associated plasma protein‐A (PAPP‐A) ≥ 1 multiple of the median, or trisomy 21 risk of ≤ 1 in 1000, the prevalence of pCNVs exceeded significantly the prevalence of trisomies 21, 18 and 13. Pregnancies affected by a pCNV had significantly increased NT and decreased levels of the maternal biomarkers PAPP‐A and β‐human chorionic gonadotropin compared with unaffected pregnancies. However, only 23% of these pregnancies screened positive on cFTS and 51% of pCNVs were not detected until after birth. Among high‐risk pregnancies, pCNVs comprised 14% of diagnosed aberrations, and when other atypical aberrations were considered, conventional NIPT (screening for trisomies 21, 18 and 13 and monosomy X) would miss 27% of all pathogenic aberrations diagnosed from invasive testing following a high‐risk cFTS result. Thus, 1 in 26 pregnancies at high risk following cFTS would be affected by a chromosomal aberration despite a normal result from conventional NIPT. In a contingent screening model using NIPT for the 'intermediate'‐risk group (trisomy 21 risk of 1 in 100–299), 50% of the aberrations would be missed. In our cohort, 79% of the pCNVs diagnosed were < 5Mb and therefore not detectable using current forms of 'genome‐wide' NIPT. Conclusions: As a by‐product of screening for trisomies 21, 18 and 13, most triploidies and the majority of atypical SCAs, RATs and mosaicisms are detected before birth. However, only 23% of pCNVs are associated with a high‐risk result according to cFTS and only half are diagnosed before birth. Replacing invasive testing with NIPT for high‐risk pregnancies would substantially decrease the first‐trimester detection of pathogenic chromosomal anomalies. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

The incident of Chernobyl Nuclear Power Plant (CNPP) explosion has pioneered a plethora of studies unfolding various biological effects of radiation stress on several living systems. Determining radiation dose rates at which both acute and chronic biological effects occur in different biological systems will aid in the ex-situ generation of radiation-tolerant organisms. So far, the accumulation of data on different radiation doses from Chernobyl area demonstrating various biological impacts has not been documented altogether vastly. Therefore, this review aims to document the recorded doses in CNPP over the years at which different biological changes have been observed in plants, soil, aquatic organisms, birds, and animals. A total of 72 peer-reviewed papers obtained from PubMed, Google Scholar, Scopus, and Research4life were included in this review. A few factors have come under attention in this review. Firstly, plant and soil systems combinedly showed the most published studies after the catastrophe where plants showed a higher frequency of DNA methylation in their genome to resist radiation stress. Secondly, reduced species abundance, chromosomal aberrations, increased sterility, and mortality were mostly observed in the aftermath of Chernobyl catastrophe among plants, soil, aquatic organisms, birds, and small mammals. Furthermore, major scares of data after 2018 were prominently observed. Very few studies on radiation dose levels after 2018 are available. Hence, a major research area has emerged for radiation biologists to study present radiation levels and any genetic changes in the recent generation of the original victim species. This will help provide a standard dataset that can act as a reference resource for radiation biologists and future research on the impact of both acute and chronic radiation on the different biological systems. [ABSTRACT FROM AUTHOR]

Purpose: Nowadays people are exposed to radiation due to various reasons, including natural, diagnostic, occupational or accidental exposure. High level of exposure to ionizing radiation can be fatal to human body. Synthetic drugs used to prevent radiation-induced damage are toxic in nature. Recently, Herbal drugs are being screened as an alternative due to their mechanism of action. Garcinia indica (G. indica) is one of the traditional medicinal plant which contains phytochemicals having several medicinal properties. Materials and methods: In this study, G. indica extract was observed for its modulatory effect against 3 Gray (Gy) gamma radiation-induced damages in human peripheral blood lymphocytes. Various concentrations of G. indica extract ranging from 1 to 25 µg/mL was added to the blood post irradiation at 0 hr. Chromosomal aberration (CA) and Cytochalasin B blocked Micronuclei Cytome (CBMN) Assay were performed as per standard procedure. Results: Radiomodulatory effect of Garcinia indica fruit rind extract (GIFRE) on CA and MN formation was observed in this study. Treatment of GIFRE did not affect the mitotic index. Positive inhibition percentages for dicentrics, total chromosomal aberrations and micronuclei were observed except for one instance. Conclusion: Owing to the various properties of Garcinia extracts, it makes it a potential candidate to be tested for its radiomodulatory effect. Based on the results observed in this preliminary study, it could act as a radiomodulatory agent. Radiomodulatory effect of GIFRE could possibly serve it as a potential herbal medicinal alternative to current drugs. However, results of this study need to be validated on larger sample size. [ABSTRACT FROM AUTHOR]

Five Phyllanthus species were characterized using a fluorochrome chromosome banding technique with CMA and DAPI. This genus displayed a range of somatic chromosomal counts, including 2n = 2x = 26 (diploid) in P. acidus, P. niruri, and P. reticulatus; 2n = 6x = 48 (hexaploid) in P. urinaria; and 2n = 10x = 100 (decaploid) in P. emblica (wild and cultivated varieties), which exhibited a multi-basic chromosome number. The centromeric and terminal regions of the chromosomes contained most of the CMA and DAPI bands, indicating that GC- and AT-rich repeats had accumulated in these locations. The diversity based on the heterochromatin distribution patterns made it possible to use the CMA and DAPI banding approaches to analyze and characterize these five Phyllanthus species. [ABSTRACT FROM AUTHOR]

Ochratoxin A (OTA), as one of the most important and harmful mycotoxins, is classed as possible human carcinogen (group 2B). As we all know, DNA damage may cause genomic instability, cell cycle disorder, activation of DNA damage pathway, and stimulation of DNA repair system. To explore the roles of DNA damage repair protein (hMLH1) on OTA-induced G 2 arrest, the DNA damage, chromosome aberration, cell cycle distribution and p53-p21 signaling pathway were evaluatd after different time OTA exposure (6, 12, 24, 48 h) in immortalized human gastric epithelial cells (GES-1). Our results demonstrated that OTA exposure could trigger genomic instability, DNA damage and G 2 phase arrest of GES-1 cells. At the same time, OTA treatment could increase the expression of hMLH1, and induce phosphorylation of the p53 protein, as well as p21, in response to DNA damage. Finally, inhibition of hMLH1 by siRNA effectively prevented the activation of p53-p21 signaling pathway and rescued the G 2 arrest elicited by OTA. This study demonstrated that hMLH1-p53-p21 signaling pathway played an important role in DNA damage and G 2 cell cycle arrest the mediated by OTA in GES-1 cells. • OTA treatment for different amounts of time in GES-1 cells could induce chromosomal aberrations, DNA damage and G 2 /M phase arrest. • OTA treatment for different amounts of time induced GES-1 cells to arrest at G 2 /M phase by regulating the expression of Cdc2, p-Cdc2 and CyclinB1. • The hMLH1-p53-p21 signaling pathway play an important role in OTA-caused G 2 phase arrest in GES-1 cells. [ABSTRACT FROM AUTHOR]

Background: This study systematically reviewed the causes of child death across different age groups based on the International Classification of Diseases, 10th Revision (ICD-10) criteria. Methods: A comprehensive search was conducted in seven electronic databases and two search engines to identify all studies examining child mortality in any part of Iran or the entire country. Hand searching, gray literature, and bibliographies were also utilized. Data were synthesized descriptively and through meta-analysis. Results: A total of 35 studies were included, encompassing 58,519 death cases across various age groups. According to the ICD-10 classification, the most common causes of Neonatal Mortality Rates (NMR) were pregnancy, childbirth, and puerperium-related conditions (41.1%), congenital malformations (19.2%), and certain conditions originating in the perinatal period (14.5%). For Infant Mortality Rates (IMR), the leading causes were congenital malformations (44.0%), pregnancy, childbirth, and related conditions (14.5%), and respiratory and cardiovascular diseases (8.7%). In the age group of 28 days to 5 years, the primary causes of death were pregnancy, childbirth, and puerperium-related issues (27.5%), congenital malformations and chromosomal abnormalities (21.6%), and respiratory and cardiovascular disease (9.3%). For children aged 1 to 5 years, congenital malformations (29.1%), external causes (19.6%), and respiratory and cardiovascular disorders (7.2%) were the most significant causes of death. The meta-analysis revealed that immaturity [0.171 (PI: 0.032–0.561)] in infants aged 0–28 days, and congenital malformations in the age groups of 28 to 1 year [0.261 (PI: 0.166–0.385)] and 28 to 5 years [0.173 (PI: 0.078–0.342)] were the leading causes of death. Conclusions: The findings of this study provide valuable insights for priority-setting interventions aimed at reducing child mortality according to the prevalence rate of specific causes in different age groups. [ABSTRACT FROM AUTHOR]

ABSTRACT Clonal evolution (CE) is a driving force behind the development and progression of acute myeloid leukemia (AML). Advances in molecular and cytogenetic assays have improved the depth and breadth of detection of CE in AML, which is defined here as a detected change in cytogenetic or molecular profile at relapsed or refractory (RR) disease. In this study, we demonstrate the clinical impact of CE in a cohort of patients with RR AML treated between 2013 and 2023. We discovered CE is significantly more frequent in relapsed disease (58.2%, [46.6%, 69.2%]) than in refractory disease (21.1%, [14.4%, 29.2%], p < 0.001). CE negatively impacts prognosis when detected by conventional karyotyping in refractory disease (4.2 vs. 13.9 months, p < 0.011). In contrast with prior literature, CE had no impact on overall survival if detected in relapsed disease. Surprisingly, those who achieved negative measurable residual disease (MRD) were no more likely to eliminate their original clone than those who did not (p = 1). We found several cytogenetic and molecular signatures which may predispose to CE: aberrations of chromosome 17, trisomy 8, TP53, KRAS, and FLT3‐TKD. Finally, physicians were less likely to retreat those with CE with IC after receiving IC as first‐line therapy (35.0% vs. 70.9%, p = 0.004). This study illustrates the role of CE in chemotherapy‐resistant AML; we identify unique cytogenetic and molecular signatures that define a subset of patients associated with a dismal prognosis. As next‐generation sequencing panels expand and new methods to characterize cytogenetic abnormalities emerge, our findings establish a basis for future studies investigating the prognostic and therapeutic impact of CE. [ABSTRACT FROM AUTHOR]

AbstractTo quantitatively investigate the effects of chronic low-dose internal exposure to Cesium-137 on DNA damage, carcinogenicity, and offspring over multiple generations. The potential genetic risk in humans was predicted based on next-generation murine mutation rates to confirm the reasonableness of the current Cesium-137 dose limits for food. Cesium-137 (100 Bq/mL) was provided in drinking water to A/J mice, facilitating chronic, low-dose, low-dose-rate internal exposure through sibling mating over 25 generations (G25). The A/J mice were compared with a control strain with the same origin ancestry (no Cesium-137 water) for DNA double-strand breaks (DSBs), oxidative stress, chromosome aberrations, micronucleus test results, whole genome analysis, carcinogenicity, tumor growth rate, and immune competence. Compared to the control group, DNA DSBs and oxidative stress were significantly increased in the Cesium-137 group. However, no significant differences were observed between the groups regarding chromosome aberration, micronuclei, or the whole genome sequence mutation analysis. Although the carcinogenic rate did not differ between the groups, the rate of tumor growth was significantly suppressed in the Cesium-137 group. The anti-tumor cytokine trend in the Cesium-137 group likely contributed to this effect. No pathological or genetic effects were observed in the offspring of mice drinking water containing 100 Bq/mL Cesium-137 after G25. The contribution of low dose-rate radiation to carcinogenicity was not additive but growth-inhibitory. Although the negative data are not conclusive, these findings are deemed highly reliable. [ABSTRACT FROM AUTHOR]

(1) Background: Nonobstructive azoospermia (NOA) etiologies affect the sperm retrieval rate (SRR) by microdissection testicular sperm extraction (micro-TESE) and the clinical outcomes following intracytoplasmic sperm injection (ICSI); (2) Methods: We investigated seven NOA etiologies. The SRR and clinical outcomes of 627 patients were analyzed between November 2017 and July 2022 in the Reproductive and Genetic Hospital of China International Trust and Investment Corporation-Xiangya (CITIC-Xiangya); (3) Results: The overall SRR was 39.4% (247/627). The SRR according to NOA etiologies were: Y chromosome azoospermia factor c microdeletions (26/46, 56.5%), Klinefelter syndrome (KS), 36/85, 42.4%), idiopathic (110/398, 27.6%), cryptorchidism (20/29, 69.0%), chromosome anomalies (7/13, 53.9%), orchitis (45/50, 90.0%), and cancer (3/6, 50.0%). The SRR were different for spermatogonia arrest (26/96, 27.1%), maturation arrest (76/177, 42.9%), and SCOS (30/80, 37.5%) according to histological examinations. The clinical pregnancy rate was similar among the NOA etiologies. The high-quality embryo rate differed between successful (54.7%) and unsuccessful (40.9%) pregnancies. Moreover, the successfully pregnant women (28.99 years) were younger than the unsuccessfully pregnant ones (30.92 years); (4) Conclusions: The SRR from patients with NOA was associated with the etiology and histological categories, while the clinical outcome was associated with the high-quality embryo rate and the female partner's age. [ABSTRACT FROM AUTHOR]

Simple Summary: The diagnosis and treatment of ovarian cancer still pose many problems; so, it is important to search for effective biomarkers that will allow for the detection of changes in the early stages of the disease. There is more and more talk about the use of circulating tumor DNA in oncology as a promising biomarker and an aid in tailoring individual therapy to patients. We describe what changes we can observe in ctDNA in patients with ovarian cancer and how we can use this information in diagnosis and therapy. Ovarian cancer is the deadliest of all gynecological diseases because its diagnosis and treatment still pose many problems. Surgical excision, hormone therapy, radiation, chemotherapy, or targeted therapy for eradicating the main tumor and halting the spread of metastases are among the treatment options available to individuals with ovarian cancer, depending on the disease's stage. Tumor DNA that circulates in a patient's bodily fluids has been studied recently as a possible novel biomarker for a number of cancers, as well as a means of quantifying tumor size and evaluating the efficacy of cancer therapy. The most significant alterations that we could find in the ctDNA of ovarian cancer patients—such as chromosomal instability, somatic mutations, and methylation—are discussed in this review. Additionally, we talk about the utility of ctDNA in diagnosis, prognosis, and therapy response prediction for these patients. [ABSTRACT FROM AUTHOR]

High-grade B-cell lymphoma with 11q aberration (HGBL-11q) is a distinct lymphoma entity according to the 5th edition of the WHO classification of hematolymphoid tumors. It lacks MYC translocation but carries proximal gains and/or telomeric losses of chromosome 11q. This rare type of B-cell lymphoma is less frequently reported in people living with HIV (PLWH), and its exact frequency remains unclear. Our goal was to retrospectively analyze its frequency in a cohort of aggressive B-cell lymphomas in PLWH, including Burkitt lymphoma (BL, n = 35), diffuse large B-cell lymphoma (DLBCL, n = 48), high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS, n = 13), which was diagnosed as AIDS-related lymphoma (ARL) at our institution. In total, 10/96 (10.4%) cases harbored the typical 11q aberration pattern, predominantly those that had been classified as BL (6/35, 17.1%), DLBCL (2/48, 4.2%), and HGBL, NOS (2/13, 15.4%). We also evaluated 7 cases of AIDS-related HGBL-11q (AR-HGBL-11q) reported in the literature. The median age of our cohort was 35 years, and all the patients were male. Most cases (70%) had a history of HIV infection for over 1 year, and all were involved in lymph nodes (100%), frequently involved extranodal sites (60%), and Ann Arbor stage III/IV. In histomorphology, the cases exhibited diverse cytological features, reminiscent of BL (6 cases), DLBCL (2 cases), and HGBL (2 cases). A comparison of the combined cohort of 17 AR-HGBL-11q cases with 11 ARL cases that lacked both MYC rearrangement and 11q aberration at our institution showed that HGBL-11q cases were characterized by strikingly coarse apoptotic debris (P < 0.001), background rich in eosinophils (P = 0.002), higher expression of the germinal centre marker LMO2 (P = 0.080), lower expression of MUM1 (P = 0.004), BCL2 (P = 0.007), and LEF1 (P = 0.080), and lower positivity for EBER in situ hybridisation (P = 0.027). Notably, one case in our series was EBV-positive, a finding not previously reported in the literature. Furthermore, comparing the prognosis between these two groups, AR-HGBL-11q showed a relatively favorable prognosis (P = 0.15), although the difference was not statistically significant. We analyzed this rare lymphoma entity in the HIV setting and highlighted the importance of integrating histomorphological and immunophenotypic features in its diagnosis and classification. [ABSTRACT FROM AUTHOR]

Objective: This work aimed to investigate the potential correlation between chromosomal polymorphisms and various reproductive abnormalities. Methods: We examined 21,916 patients affected by infertility who sought care at the Department of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University between January 2018 and December 2022. A total of 2227 individuals identified as chromosomal polymorphism carriers constituted the polymorphism group, and 2245 individuals with normal chromosome karyotypes were randomly selected to form a control group. Clinical manifestations, histories of spontaneous miscarriage, abnormal reproductive developments, fetal abnormalities, and male sperm quality anomalies were statistically compared between these two groups. Results: Of the 21,916 patients analyzed, 2227 displayed chromosomal polymorphism, representing a 10.16% detection rate. Amongst the male patients, 1622 out of 10,827 exhibited polymorphisms (14.98%), whereas 605 out of 11,089 females showed polymorphisms (5.46%). Female carriers in the polymorphism group, showed statistically significant increased rates of spontaneous abortion (29.75% vs. 18.54%), fetal anomalies (1.32% vs. 0.81%), and uterine abnormalities compared with the control group (1.32% vs. 0.81%). Male carriers in the polymorphism group had higher rates of spontaneous abortion in partners (22.87% vs. 10.37%), fetal anomalies (1.97% vs. 0.25%), compromised sperm quality (41.74% vs. 7.18%), testicular underdevelopment (2.28% vs. 0.92%), and hypogonadotropic hypogonadism (0.62% vs. 0.37%) compared with the control group. Conclusion: Chromosomal polymorphisms may have a certain negative effect on reproductive irregularities, including spontaneous abortions, fetal anomalies, and reduced sperm quality in males. Their clinical effects deserve further investigation. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to evaluate the occurrence of clinically relevant (sub)microscopic chromosomal aberrations in fetuses with the nuchal translucency (NT) range from 3.0 to 3.4 mm, which would be potentially missed by cfDNA testing. Methods: A retrospective data analysis of 271 fetuses with NT between 3.0 and 3.4 mm and increased first trimester combined test (CT) risk in five cohorts of pregnant women referred for invasive testing and chromosomal microarray was performed. Results: A chromosomal aberration was identified in 18.8% fetuses (1:5; 51/271). In 15% (41/271) of cases, trisomy 21, 18, or 13 were found. In 0.7% (2/271) of cases, sex chromosome aneuploidy was found. In 1.1% (3/271) of cases, CNV >10 Mb was detected, which would potentially also be detected by genome-wide cfDNA testing. The residual risk for missing a submicroscopic chromosome aberration in the presented cohorts is 1.8% (1:54; 5/271). Conclusion: Our results indicate that a significant number of fetuses with increased CT risk and presenting NT of 3.0–3.4 mm carry a clinically relevant chromosomal abnormality other than common trisomy. Invasive testing should be offered, and counseling on NIPT should include the test limitations that may result in NIPT false-negative results in a substantial percentage of fetuses. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although recent in vitro experimental results have raised the question of whether maternal exposure to per- and polyfluoroalkyl substances (PFAS) may be a potential environmental risk factor for chromosomal abnormalities, epidemiological studies investigating these associations are lacking. OBJECTIVES: This study examined whether prenatal PFAS exposure is associated with a higher prevalence of chromosomal abnormalities among offspring. METHODS: We used data from the Japan Environment and Children’s Study, a nationwide birth cohort study, and employed logistic regression models to examine the associations between maternal plasma PFAS concentrations in the first trimester and the diagnosis of chromosomal abnormalities in all births (artificial abortions, miscarriages, stillbirths, and live births) up to 2 years of age. In addition, we examined associations with mixtures of PFAS using multipollutant models. RESULTS: The final sample consisted of 24,724 births with singleton pregnancies, of which 44 confirmed cases of chromosomal abnormalities were identified (prevalence: 17.8/10,000 births). When examined individually, exposure to perfluorononanoic acid (PFNA) and perfluorooctane sulfonic acid (PFOS) showed positive associations with any chromosomal abnormalities with age-adjusted odds ratios of 1.81 (95% CI: 1.26, 2.61) and 2.08 (95% CI: 1.41, 3.07) per doubling in concentration, respectively. These associations remained significant after Bonferroni correction, although they did not reach the adjusted significance threshold in certain sensitivity analyses. Furthermore, the doubling in all PFAS included as a mixture was associated with chromosomal abnormalities, indicating an age-adjusted odds ratio of 2.25 (95% CI: 1.34, 3.80), with PFOS as the predominant contributor, followed by PFNA, perfluoroundecanoic acid (PFUnA), and perfluorooctanoic acid (PFOA). DISCUSSION: The study findings suggested a potential association between maternal exposure to PFAS, particularly PFOS, and chromosomal abnormalities in offspring. However, the results should be interpreted cautiously, because selection bias arising from the recruitment of women in early pregnancy may explain the associations. [ABSTRACT FROM AUTHOR]

Intellectual disability (ID) is a prevalent neurodevelopmental disorder characterized by neurodevelopmental defects such as the congenital impairment of intellectual function and restricted adaptive behavior. However, genetic studies have been significantly hindered by the extreme clinical and genetic heterogeneity of the subjects under investigation. With the development of gene sequencing technologies, more genetic variations have been discovered, assisting efforts in ID identification and treatment. In this review, the physiological basis of gene variations in ID is systematically explained, the diagnosis and therapy of ID is comprehensively described, and the potential of genetic therapies and exercise therapy in the rehabilitation of individuals with intellectual disabilities are highlighted, offering new perspectives for treatment approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: Genomic rearrangements are chromosomal abnormalities that alter the arrangement of genes and are important for diagnosing multiple cancer types and guiding therapy selection. However, current diagnostic tests may not detect all genomic rearrangements. Hi-C sequencing is a promising new method for detecting genomic rearrangements. First, we examined whether Hi-C can detect known genomic rearrangements in pediatric leukemia and sarcoma specimens. Next, we evaluated whether Hi-C can detect genomic rearrangements that were not found using standard diagnostic testing. Hi-C showed complete agreement with other diagnostic methods in identifying known rearrangements. Hi-C also detected previously unknown genomic rearrangements in 5/11 pediatric leukemia cases that could impact diagnosis, prognosis, or treatment choices. These data suggest Hi-C could be beneficial for medical diagnostic testing of pediatric cancers, but more extensive clinical validation is needed. Hi-C sequencing is a DNA-based next-generation sequencing method that preserves the 3D genome conformation and has shown promise in detecting genomic rearrangements in translational research studies. To evaluate Hi-C as a potential clinical diagnostic platform, analytical concordance with routine laboratory testing was assessed using primary pediatric leukemia and sarcoma specimens. Archived viable and non-viable frozen leukemic cells and formalin-fixed paraffin-embedded (FFPE) tumor specimens were analyzed. Pediatric acute myeloid leukemia (AML) and alveolar rhabdomyosarcoma (A-RMS) specimens with known genomic rearrangements were subjected to Hi-C to assess analytical concordance. Subsequently, a discovery cohort consisting of AML and acute lymphoblastic leukemia (ALL) cases without known genomic rearrangements based on prior clinical diagnostic testing was evaluated to determine whether Hi-C could detect rearrangements. Using a standard sequencing depth of 50 million raw read-pairs per sample, or approximately 5X raw genomic coverage, we observed 100% concordance between Hi-C and previous clinical cytogenetic and molecular testing. In the discovery cohort, a clinically relevant gene fusion was detected in 45% of leukemia cases (5/11). This study provides an institutional proof of principle evaluation of Hi-C sequencing to medical diagnostic testing as it identified several clinically relevant rearrangements, including those that were missed by current clinical testing workflows. [ABSTRACT FROM AUTHOR]

Centromeric localization of evolutionarily conserved CENP-A (Cse4 in Saccharomyces cerevisiae) is essential for chromosomal stability. Mislocalization of overexpressed CENP-A to noncentromeric regions contributes to chromosomal instability in yeasts, flies, and humans. Overexpression and mislocalization of CENP-A observed in many cancers are associated with poor prognosis. Previous studies have shown that F-box proteins, Cdc4 and Met30 of the Skp, Cullin, F-box ubiquitin ligase cooperatively regulate proteolysis of Cse4 to prevent Cse4 mislocalization and chromosomal instability under normal physiological conditions. Mck1 -mediated phosphorylation of Skp, Cullin, F-box- Cdc4 substrates such as Cdc6 and Rcn1 enhances the interaction of the substrates with Cdc4. Here, we report that Mck1 interacts with Cse4 , and Mck1 -mediated proteolysis of Cse4 prevents Cse4 mislocalization for chromosomal stability. Our results showed that mck1 Δ strain overexpressing CSE4 (GAL- CSE4) exhibits lethality, defects in ubiquitin-mediated proteolysis of Cse4 , mislocalization of Cse4 , and reduced Cse4 – Cdc4 interaction. Strain expressing GAL- cse4 -3A with mutations in three potential Mck1 phosphorylation consensus sites (S10, S16, and T166) also exhibits growth defects, increased stability with mislocalization of Cse4 -3A, chromosomal instability, and reduced interaction with Cdc4. Constitutive expression of histone H3 (Δ16H3) suppresses the chromosomal instability phenotype of GAL- cse4 -3A strain, suggesting that the chromosomal instability phenotype is linked to Cse4 -3A mislocalization. We conclude that Mck1 and its three potential phosphorylation sites on Cse4 promote Cse4 – Cdc4 interaction and this contributes to ubiquitin-mediated proteolysis of Cse4 preventing its mislocalization and chromosomal instability. These studies advance our understanding of pathways that regulate cellular levels of CENP-A to prevent mislocalization of CENP-A in human cancers. [ABSTRACT FROM AUTHOR]

Interspecific F1 hybrids between Asian (Oryza sativa) and African rice (Oryza glaberrima) exhibit severe sterility caused by the accumulation of hybrid sterility genes/loci at 15 or more loci. The mechanisms underlying the hybrid sterility genes are largely unknown; however, a few genes associated with the killer–protector system, which is the system most frequently associated with hybrid sterility genes, have been identified. We previously produced fertile plants as tetraploids derived from diploid interspecific F1 hybrids through anther culture; therefore, it was suggested that hybrid sterility could be overcome following tetraploidization. We investigated whether tetraploid interspecific plants produced by crossing are fertile and tested the involvement of hybrid sterility genes in the process. Fertile tetraploid interspecific F1 hybrid plants were obtained by crossing 2 tetraploids of O. sativa and O. glaberrima. To elucidate the relationships between pollen fertility and the hybrid sterility loci in the tetraploid F1 microspores, we performed genetic analyses of the tetraploid F2 hybrids and diploid plants obtained from the microspores of tetraploid interspecific hybrids by anther culture. The result suggested that the tetraploid interspecific hybrids overcame pollen and seed infertility based on the proportion of loci with the killer–protector system present in the tetraploids. The heterozygous hybrid sterility loci with the killer–protector system in the tetraploid segregate the homozygous killed allele (16.7–21.4%), with more than three-quarters of the gametes surviving. We theoretically and experimentally demonstrated that fertile rice progenies can be grown from tetraploid interspecific hybrids. [ABSTRACT FROM AUTHOR]

Non–small cell lung cancer (NSCLC) has been found to have recurrent genetic abnormalities, and novel therapies targeting these aberrations have improved patient survival. In this study, specimens from benign tissue, primary tumors, and brain metastases were obtained at autopsy from a 55-year-old White female patient diagnosed with NSCLC and were examined using next-generation sequencing (NGS) and chromosomal microarray assay (CMA). No genetic aberrations were noted in the benign tissue; however, NGS identified a mutation in the KRAS proto-oncogene, GTPase (KRAS): KRAS exon 2 p.G12D in primary and metastatic tumor specimens. We observed 7 DNA copy number aberrations (CNAs) in primary and metastatic tumor specimens; an additional 7 CNAs were exclusively detected in the metastatic tumor specimens. These DNA alterations may be genetic drivers in the pathogenesis of the tumor specimen from our patient and may serve as biomarkers for the classification and prognosis of NSCLC. [ABSTRACT FROM AUTHOR]

Key message: In Cyrtanthus mackenii, development of embryo and endosperm were differentially affected by fertilization of male gametes with DNA damage and mutations. Pollen irradiation with ionizing radiations has been applied in plant breeding and genetic research, and haploid plant induction has mainly been performed by male inactivation with high-dose irradiation. However, the fertilization process of irradiated male gametes and the early development of embryo and endosperm have not received much attention. Heavy-ion beams, a type of radiation, have been widely applied as effective mutagens for plants and show a high mutation rate even at low-dose irradiation. In this study, we analyzed the effects of male gametes of Cyrtanthus mackenii irradiated with a carbon-ion beam at low doses on fertilization. In immature seeds derived from the pollination of irradiated pollen grains, two types of embryo sacs were observed: embryo sac with a normally developed embryo and endosperm and embryo sac with an egg cell or an undivided zygote and an endosperm. Abnormalities in chromosome segregation, such as chromosomal bridges, were observed only in the endosperm nuclei, irrespective of the presence or absence of embryogenesis. Therefore, in Cyrtanthus, embryogenesis is strongly affected by DNA damage or mutations in male gametes. Moreover, various DNA contents were detected in the embryo and endosperm nuclei, and endoreduplication may have occurred in the endosperm nuclei. As carbon-ion irradiation causes chromosomal rearrangements even at low doses, pollen irradiation can be an interesting tool for studying double fertilization and mutation heritability. [ABSTRACT FROM AUTHOR]

Imagawa-Matsumoto syndrome (IMMAS; MIM #618786) is an autosomal dominant syndrome characterized by overgrowth, dysmorphic features, musculoskeletal abnormalities, developmental delay, and intellectual disability. The first case was reported in 2017 and has subsequently been diagnosed in only another 12 patients. We also present the first IMMAS patient from Turkey. A 19-year-old female was admitted to the neurology outpatient clinic due to a behavioral disorder and intellectual disability. Her physical examination revealed macrocephaly and dysmorphic features like a round face, broad forehead, hypertelorism, and variable skeletal anomalies such as flat feet, clinodactyly, and macrocephaly. Cranial magnetic resonance imaging (MRI) showed agenesis of the corpus callosum and polymicrogyria. Chromosomal analysis results were consistent with a normal constitutional female karyotype and microarray analysis showed a de novo 1.5-MB size deletion on the long arm of chromosome 17; band q11.2 encompassing the Polycomb Repressive Complex 2 Subunit (SUZ12 gene, MIM *606245). This report will contribute to the limited information in the literature. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the clinical features and perinatal outcomes of antenatally diagnosed fetuses with omphalocele and gastroschisis. Material and Methods: This was a retrospective, single-center, cohort study of prenatally diagnosed fetuses with omphalocele and gastroschisis followed-up and delivered at a university hospital. Demographic, pregnancy, birth and perinatal outcomes were compared between gastroschisis and omphalocele. Results: A total of 75 fetuses with omphalocele and 21 cases with gastroschisis were evaluated. The mean maternal age of women carrying a fetus with omphalocele was significantly higher than the women with gastroschisis (p=0.001). Associated structural anomalies were found in 53.3% and 4.7% of fetuses with omphalocele and gastroschisis, respectively (p<0.001). The rate of chromosomal anomaly was 8.3% in pregnancies with omphalocele. In liveborn pregnancies, the mean gestational age at delivery and birth weight did not differ between the study groups. Time to postoperative oral intake, duration of parenteral nutrition and length of hospital stay were significantly longer in babies with gastroschisis than omphalocele (p<0.01). Rates of termination, intrauterine, neonatal and infant death of fetuses with omphalocele were 25.3%, 6.7%, 10.7% and 2.7% respectively. Time to postoperative oral intake, duration of parenteral nutrition and duration of hospitalization were significantly longer in babies with complex compared to simple gastroschisis (p<0.01). Survival rates were 95.2%, 82.9% and 20% in fetuses with gastroschisis, isolated and non-isolated omphalocele, respectively. Conclusion: Associated structural and chromosomal anomalies were significantly more common in fetuses with omphalocele compared to those with gastroschisis. Prognosis of fetuses with omphalocele depended on the associated structural and chromosomal anomalies, whereas bowel compromise was the main determining factor in gastroschisis. [ABSTRACT FROM AUTHOR]

Vanadium is a strategic metal that has many important industrial applications and is generated by the use of burning fossil fuels, which inevitably leads to their release into the environment, mainly in the form of oxides. The wastes generated by their use represent a major health hazard. Furthermore, it has attracted attention because several genotoxicity studies have shown that some vanadium compounds can affect DNA; among the most studied compounds is vanadium pentoxide, but studies in vivo with oxidation states IV and III are scarce and controversial. In this study, the genotoxic and cytotoxic potential of vanadium oxides was investigated in mouse bone marrow cells using structural chromosomal aberration (SCA) and mitotic index (MI) test systems. Three groups were administered vanadium(IV) tetraoxide (V2O4) intraperitoneally at 4.7, 9.4 or 18.8 mg/kg, and three groups were administered vanadium(III) trioxide (V2O3) at 4.22, 8.46 or 16.93 mg/kg body weight. The control group was treated with sterile water, and the positive control group was treated with cadmium(II) chloride (CdCl2). After 24 h, all doses of vanadium compounds increased the percentage of cells with SCA and decreased the MI. Our results demonstrated that under the present experimental conditions and doses, treatment with V2O4 and V2O3 induces chromosomal aberrations and alters cell division in the bone marrow of mice. [ABSTRACT FROM AUTHOR]

Inhalation exposures to dihydroxyacetone (DHA) occur through spray tanning and e-cigarette aerosols. Several studies in skin models have demonstrated that millimolar doses of DHA are cytotoxic, yet the genotoxicity was unclear. We examined the genotoxicity of DHA in cell models relevant to inhalation exposures. Human bronchial epithelial cells BEAS-2B, lung carcinoma cells A549, cardiomyocyte Ac16, and hepatocellular carcinoma HepG3 were exposed to DHA, and low millimolar doses of DHA were cytotoxic. IC90 DHA doses induced cell cycle arrest in all cells except the Ac16. We examined DHA's genotoxicity using strand break markers, DNA adduct detection by Repair Assisted Damage Detection (RADD), metaphase spreads, and a forward mutation assay for mutagenesis. Similar to results for skin, DHA did not induce significant levels of strand breaks. However, RADD revealed DNA adducts were induced 24 h after DHA exposure, with BEAS-2B and Ac16 showing oxidative lesions and A549 and HepG3 showing crosslink-type lesions. Yet, only low levels of reactive oxygen species or advanced glycation end products were detected after DHA exposure. Metaphase spreads revealed significant increases in chromosomal aberrations in the BEAS-2B and HepG3 with corresponding changes in ploidy. Finally, we confirmed the mutagenesis observed using the supF reporter plasmid. DHA increased the mutation frequency, consistent with methylmethane sulfonate, a mutagen and clastogen. These data demonstrate DHA is a clastogen, inducing cell-specific genotoxicity and chromosomal instability. The specific genotoxicity measured in the BEAS-2B in this study suggests that inhalation exposures pose health risks to vapers, requiring further investigation. [ABSTRACT FROM AUTHOR]

Background: Autism and autistic traits onset in childhood but persist into adulthood. Little is known about how genetic and environmental factors influence autism and autistic traits into adulthood. We aimed to determine age effects on the heritability of clinically diagnosed autism and the etiological stability of autistic traits from childhood to adulthood using twin methods. Methods: From 23,849 twin pairs in the Swedish Twin Register born between 1959 and 2010, we identified 485 individuals (1.01%, 31.5% female) with a clinical autism diagnosis. We estimated and compared the relative contribution of genetic, shared, and nonshared environmental influences to autism in childhood and adulthood. We further used multivariate twin analysis with four measurement points among 1,348 twin pairs in the longitudinal Twin Study of Child and Adolescent Development to assess the phenotypic and etiological stability of autistic traits – measured with three scales from the Child Behavior Checklist – from childhood to adulthood. Results: Autism heritability was comparable from childhood, (96% [95% CI, 76–99%]) to adulthood (87% [67–96%]). Autistic traits were moderately stable (phenotypic correlation = 0.35–0.61) from childhood to adulthood, and their heritability varied between 52 and 71%. We observed stable as well as newly emerging genetic influences on autistic traits from ages 8–9 to 19–20, and unique nonshared environmental influences at each age. Conclusions: Genetic factors are important for autism and autistic traits in adulthood and separate genetic studies in adults are warranted. [ABSTRACT FROM AUTHOR]

Background: Chronic myeloid leukemia (CML), a myeloproliferative neoplasm defined by the BCR::ABL1 fusion gene arising from the Philadelphia chromosome (Ph) translocation t(9:22)(q34;q11), exhibits diverse clinical courses often influenced by additional chromosomal aberrations (ACAs). This report presents a case of CML harboring a novel four-way Ph translocation involving the X chromosome, offering insights into the interplay between complex karyotypes and treatment response and emphasizing the need for further research into the role of ACAs in CML management. Methods: A 42-year-old man diagnosed with CML in the accelerated phase presented a novel four-way Ph translocation involving chromosomes X, 5, 9, and 22: 46, Y,t(X;5;9;22)(q26;q15;q34;q11.2). Despite achieving a major molecular response initially with imatinib and nilotinib, BCR::ABL1 levels (international scale) increased up to 24.0%, which prompted the use of second-line nilotinib. Results: Follow-up bone marrow (BM) studies revealed clonal evolution with trisomy 8 and an unclassified ABL1 mutation (E292V), potentially contributing to resistance. Though a transient major molecular response (MMR) occurred after a switch to third-line dasatinib, this change failed to achieve a deep molecular response, and BCRABL1 levels were elevated above the MMR. Conclusions: This case highlights the challenge of ACAs impacting CML treatment response and prognosis. Limited knowledge exists on complex Ph translocations involving the X chromosome, but this report contributes data for further research. Understanding ACA effects on therapeutic response and prognosis requires a detailed study of such complex chromosomal aberrations. [ABSTRACT FROM AUTHOR]

Disorders of sex development (DSD) result from intrauterine defects in sex discrimination. The clinical phenotype differs based on the disease type. Cases with ambiguous external genitalia are diagnosed at birth. However, diagnosis of cases with normal-appearing external genitalia may be delayed until puberty. Here, we report a patient with a pelvic mass and a small uterus that was diagnosed by abdominal ultrasound, in addition to the history of primary amenorrhea and physical examination suggested Swyer syndrome, confirmed by genetic karyotyping. Pathological examination of the surgically removed mass revealed dysgerminoma. Until the age of 19, the patient did not have any idea about 46, XY karyotype, and assumed to be a female. The development of dysgerminoma (as a result of the simultaneous presence of gonadal dysgenesis and Y-chromosome) was another challenge that the patient had to deal with. The diagnosis of this patient at an earlier age could have prevented the development of gonadoblastoma, by removal of the streak gonads. By the presentation of this case, we intend to increase the physician's awareness about DSDs; earlier diagnosis may help the patient deal with her disease better and reduce the risk of further complications. [ABSTRACT FROM AUTHOR]

Carbon ion radiotherapy (CIRT) for pediatric cancer is currently limited because of the unknown risk of induction of secondary cancers. Medulloblastoma of Ptch1+/– mice offers a unique experimental system for radiation-induced carcinogenesis, in which tumors are classified into spontaneous and radiation-induced subtypes based on their features of loss of heterozygosity (LOH) that affect the wild-type Ptch1 allele. The present study aims to investigate in young Ptch1+/– mice the carcinogenic effect, and its age dependence, of the low-linear energy transfer (LET, ∼13 keV/µm) carbon ions, to which normal tissues in front of the tumor are exposed during therapy. We irradiated Ptch1+/– mice at postnatal day (P) 1, 4, or 10 with 290 MeV/u carbon ions (0.05–0.5 Gy; LET, 13 keV/µm) and monitored them for medulloblastoma development. Loss of heterozygosity of seven genetic markers on chromosome 13 (where Ptch1 resides) was studied to classify the tumors. Carbon ion exposure induced medulloblastoma most effectively at P1. The LOH patterns of tumors were either telomeric or interstitial, the latter occurring almost exclusively in the irradiated groups, allowing the use of interstitial LOH as a biomarker of radiation-induced tumors. Radiation-induced tumors developed during a narrow age window (most strongly at P1 and only moderately at P4, with suppressed tumorigenesis at P10). Calculated using previous results using 137Cs gamma rays, the values for relative biological effectiveness (RBE) regarding radiation-induced tumors were 4.1 (3.4, 4.8) and 4.3 (3.3, 5.2) (mean and 95% confidence interval) for exposure at P1 and 4, respectively. Thus, the RBE of carbon ions for medulloblastoma induction in Ptch1+/– mice was higher than the generally recognized RBE of 1–2 for cell killing, chromosome aberrations, and skin reactions. [ABSTRACT FROM AUTHOR]

This study reports three patients with Cat-eye Syndrome (CES), two of which present a previous clinical diagnosis of Craniofacial microsomia (CFM). Chromosomal microarray analysis (CMA) revealed a tetrasomy of 1,7 Mb at the 22q11.2q11.21 region, which is the typical region triplicated in the CES, in all patients. The most frequent craniofacial features found in individuals with CFM and CES are preauricular tags and/or pits and mandibular hypoplasia. We reinforce that the candidate genes for CFM features, particularly ear malformation, preauricular tags/pits, and facial asymmetry, can be in the proximal region of the 22q11.2 region. [ABSTRACT FROM AUTHOR]

One way of limiting the environmental impact of food production and improving food security is to replace part of the animal‐ or plant‐based protein in the human diet with protein sourced from microorganisms. The recently discovered bacterium Xanthobacter sp. SoF1 (VTT‐E‐193585) grows autotrophically using carbon dioxide gas as the only carbon source, yielding protein‐rich biomass that can be processed further into a powder and incorporated into various food products. Since the safety of this microbial protein powder for human consumption had not been previously assessed, its genotoxic potential was evaluated employing three internationally recognized and standardized studies: a bacterial reverse mutation test, an in vitro chromosomal aberration assay in human lymphocytes, and an in vitro micronucleus test in human lymphocytes. No biologically relevant evidence of genotoxicity or mutagenicity was found. The bacterium Xanthobacter sp. SoF1 (VTT‐E‐193585) grows autotrophically using carbon dioxide as the only carbon source, yielding protein‐rich biomass. Since the safety of this microbial protein for human consumption had not been assessed, its genotoxic potential was evaluated employing three internationally recognized and standardized studies: an in vitro chromosomal aberration assay in human lymphocytes, a bacterial reverse mutation test and an in vitro micronucleus test in human lymphocytes. No biologically relevant evidence of genotoxicity or mutagenicity was found. [ABSTRACT FROM AUTHOR]

Objective: Rare coexistence of disease or pathology. Background: Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia (Ph) chromosome, which results from the fusion of the translocation of the ABL1 gene from chromosome 9 to the BCR gene located in chromosome 22, forming the BCR-ABL gene on chromosome number 22, which accounts for approximately 95% of CML cases. Complex translocation involving other chromosomes can occur. Case Report: We present a rare case of CML with a variant Ph chromosome, in which chromosome 16 was involved with the usual translocation. A 34-year-old woman presented with a history of left upper quadrant pain and excessive sweating, with no hepatosplenomegaly on examination. She was found to have leukocytosis, with elevated neutrophils (34 000/mm3), basophils (1460/mm3), and eosinophils (2650/mm3). Karyotyping showed a translocation (16;22) (q24,q11.2), and FISH analysis showed BCR-ABL fusion as a result of (9,22) translocation, with a third chromosome (chromosome 16) involved and fused with chromosome 22, with a different breakpoint, which has never been reported in the literature, affecting the long arm of chromosome 16. The patient was treated with a first-generation tyrosine kinase inhibitor (imatinib) and achieved a deep molecular remission. The repeated FISH analysis confirmed the disappearance of both translocations (9,22) and (16,22). Conclusions: The impact of the additional chromosomal aberration in CML is widely heterogeneous, and the outcome is dependent on multiple factors. Larger studies are needed to clarify the outcome in CML with variant Ph chromosomes, as most of the available data come from reported cases. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma (NB) is a heterogeneous embryonal malignancy and the deadliest tumor of infancy. It is a complex disease that can result in diverse clinical outcomes. In some children, tumors regress spontaneously. Others respond well to existing treatments. But for the high-risk group, which constitutes approximately 40% of all patients, the prognosis remains dire despite collaborative efforts in basic and clinical research. While its exact cellular origin is still under debate, NB is assumed to arise from the neural crest cell lineage including multipotent Schwann cell precursors (SCPs), which differentiate into sympatho-adrenal cell states eventually producing chromaffin cells and sympathoblasts. Methods: To investigate clonal development of neuroblastoma cell states, we performed haplotype-specific analysis of human tumor samples using single-cell multi-omics, including joint DNA/RNA sequencing of sorted single cells (DNTR-seq). Samples were also assessed using immunofluorescence stainings and fluorescence in-situ hybridization (FISH). Results: Beyond adrenergic tumor cells, we identify subpopulations of aneuploid SCP-like cells, characterized by clonal expansion, whole-chromosome 17 gains, as well as expression programs of proliferation, apoptosis, and a non-immunomodulatory phenotype. Conclusion: Aneuploid pre-malignant SCP-like cells represent a novel feature of NB. Genetic evidence and tumor phylogeny suggest that these clones and malignant adrenergic populations originate from aneuploidy-prone cells of migrating neural crest or SCP origin, before lineage commitment to sympatho-adrenal cell states. Our findings expand the phenotypic spectrum of NB cell states. Considering the multipotency of SCPs in development, we suggest that the transformation of fetal SCPs may represent one possible mechanism of tumor initiation in NB with chromosome 17 aberrations as a characteristic element. [ABSTRACT FROM AUTHOR]

This article, published in the Journal of Experimental Botany, explores the role of a DEAD-box RNA helicase called OsRH52A in the development of the female gametophyte and seed setting in rice. The study found that loss of OsRH52A led to abnormal development of the embryo sac, resulting in low seed setting. The article also discusses the importance of normal development of male and female gametophytes for successful fertilization and seed production, as well as the various factors that can cause degeneration or defects in these gametophytes. The study highlights the molecular pathway of embryo sac development and suggests potential interactions with other proteins involved in reproductive development. Additionally, the article discusses the impact of OsRH52A on the expression of downstream genes involved in megaspore development. Overall, this research provides insights into the mechanisms underlying fertility in plants and has implications for hybrid rice development. [Extracted from the article]

AbstractThe effects of XQ528 tartrate on the embryonic and fetal development of fertile Sprague-Dawley (SD) rats, along with their embryos and littermates, were evaluated using an embryo-fetus developmental toxicity assay. fertile SD rats exhibited no significant general toxic effects when administered doses of 0.25, 1.25, and 5.0 mg/kg intranasally from days 6 to 15 of gestation. The genotoxicity of the compound was evaluated through an amalgam of tests that included the Ames test, the Chinese hamster ovary (CHO) cell chromosome aberration test, and the micronucleus test in ICR mice. The results from the Ames test indicated non-mutagenicity at concentrations of 5000, 500, 50.0, 5.0, and 0.5 μg/dish across strains TA97, TA98, TA100, TA102, and TA1535. Additionally, the chromosomal aberration rates in CHO cells were not significantly altered at concentrations of 50.5, 101.0, and 202.0 μg/mL. No micronuclei induction was observed in ICR mice at dosage levels of 11.25, 22.50, and 45.00 mg/kg post intranasal administration. In conclusion, the no observed adverse effect level (NOAEL) for developmental toxicity of XQ528 tartrate in fertile SD rats, embryos, and littermates under the test conditions in this study was established at 5.0 mg/kg/day. Under these test conditions, XQ528 tartrate did not exhibit any significant genotoxic or carcinogenic potential. [ABSTRACT FROM AUTHOR]

Backgroud: A systematic analysis was conducted to investigate the molecular etiology of fetal cleft lip and/or palate (CL/P) and the association between various types of CL/P and copy number variations (CNVs), as well as their impact on birth outcomes. Methods: In this retrospective study conducted between January 2016 and July 2022, a cohort of pregnancies diagnosed with fetal CL/P was enrolled and comprehensive clinical data for all cases were extracted from our medical record database, including demographic data about the pregnancies, ultrasound findings, results of Chromosomal microarray (CMA), as well as relevant pregnant and perinatal outcomes. Results: Among the 358 cases, 32 clinically significant variants in 29 (8.1%) fetuses with CL/P were detected by CMA. In 338 singleton pregnancies, the diagnostic yield of CMA in the context of CL/P fetuses was determined to be 7.7% (26/338). CP cases exhibited a relatively higher prevalence of pathogenic/likely pathogenic CNVs at a rate of 25% (3/12), followed by CLP cases at 8.0% (23/288). Notably, the CL group did not demonstrate any pathogenic/likely pathogenic CNV findings among the examined cases (0/38). The diagnostic rate of clinically significant variants was notably higher in the non-isolated CL/P group than in the isolated CL/P group (11/33, 33.3% vs. 15/305, 4.9%, p < 0.001). Within the remaining 20 twin pregnancies, three clinically significant variants (15%) were observed. Conclusions: This study provides powerful evidence supporting the efficacy of CMA as a valuable tool for facilitating the prenatal genetic diagnosis of fetal CL/P. The presence of CP and CLP in fetal cases demonstrated a relatively higher incidence of pathogenic/likely pathogenic CNVs. Moreover, when these cases were accompanied by additional ultrasound abnormalities, the likelihood of identifying diagnostic CNVs significantly increased. Conversely, cases of CL alone might not be associated with positive CNVs. The present data may significantly enhance prenatal diagnosis accuracy and facilitate informed genetic counseling for cases of fetal CL/P. [ABSTRACT FROM AUTHOR]

Background: Deletions and partial losses of chromosome 7 (chr7) are frequent in acute myeloid leukemia (AML) and are linked to dismal outcome. However, the genomic landscape and prognostic impact of concomitant genetic aberrations remain incompletely understood. Methods: To discover genetic lesions in adult AML patients with aberrations of chromosome 7 [abn(7)], 60 paired diagnostic/remission samples were investigated by whole-exome sequencing in the exploration cohort. Subsequently, a gene panel including 66 genes and a SNP backbone for copy-number variation detection was designed and applied to the remaining samples of the validation cohort. In total, 519 patients were investigated, of which 415 received intensive induction treatment, typically containing a combination of cytarabine and anthracyclines. Results: In the exploration cohort, the most frequently mutated gene was TP53 (33%), followed by epigenetic regulators (DNMT3A, KMT2C, IDH2) and signaling genes (NRAS, PTPN11). Thirty percent of 519 patients harbored ≥ 1 mutation in genes located in commonly deleted regions of chr7—most frequently affecting KMT2C (16%) and EZH2 (10%). KMT2C mutations were often subclonal and enriched in patients with del(7q), de novo or core-binding factor AML (45%). Cancer cell fraction analysis and reconstruction of mutation acquisition identified TP53 mutations as mainly disease-initiating events, while del(7q) or −7 appeared as subclonal events in one-third of cases. Multivariable analysis identified five genetic lesions with significant prognostic impact in intensively treated AML patients with abn(7). Mutations in TP53 and PTPN11 (11%) showed the strongest association with worse overall survival (OS, TP53: hazard ratio [HR], 2.53 [95% CI 1.66–3.86]; P < 0.001; PTPN11: HR, 2.24 [95% CI 1.56–3.22]; P < 0.001) and relapse-free survival (RFS, TP53: HR, 2.3 [95% CI 1.25–4.26]; P = 0.008; PTPN11: HR, 2.32 [95% CI 1.33–4.04]; P = 0.003). By contrast, IDH2-mutated patients (9%) displayed prolonged OS (HR, 0.51 [95% CI 0.30–0.88]; P = 0.0015) and durable responses (RFS: HR, 0.5 [95% CI 0.26–0.96]; P = 0.036). Conclusion: This work unraveled formerly underestimated genetic lesions and provides a comprehensive overview of the spectrum of recurrent gene mutations and their clinical relevance in AML with abn(7). KMT2C mutations are among the most frequent gene mutations in this heterogeneous AML subgroup and warrant further functional investigation. [ABSTRACT FROM AUTHOR]

Epilepsy can be caused by a variety of causes, such as inborn errors of metabolism, organic acid disorders are the most significant type of metabolic disorders that cause seizures. The clinical manifestations of these diseases are generally nonspecific, and the types of seizures are different. Screening for multisystem clinical symptoms and identifying the underlying etiology are crucial for early treatment of epileptic seizures. This article provides a comprehensive summary of the pathogenesis, clinical features, diagnosis and treatment of epilepsy associated with organic acid metabolism disorders. Furthermore, relevant literature has also been reviewed to assist clinicians in the diagnosis of cases characterized by the coexistence of multisystemic symptoms and epileptic manifestations. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML), an aggressive malignancy of hematopoietic stem cells, is characterized by the blockade of cell differentiation, uncontrolled proliferation, and cell expansion that impairs healthy hematopoiesis and results in pancytopenia and susceptibility to infections. Several genetic and chromosomal aberrations play a role in AML and influence patient outcomes. TP53 is a key tumor suppressor gene involved in a variety of cell features, such as cell-cycle regulation, genome stability, proliferation, differentiation, stem-cell homeostasis, apoptosis, metabolism, senescence, and the repair of DNA damage in response to cellular stress. In AML, TP53 alterations occur in 5%-12% of de novo AML cases. These mutations form an important molecular subgroup, and patients with these mutations have the worst prognosis and shortest overall survival among patients with AML, even when treated with aggressive chemotherapy and allogeneic stem cell transplant. The frequency of TP53- mutations increases in relapsed and recurrent AML and is associated with chemoresistance. Progress in AML genetics and biology has brought the novel therapies, however, the clinical benefit of these agents for patients whose disease is driven by TP53 mutations remains largely unexplored. This review focuses on the molecular characteristics of TP53-mutated disease; the impact of TP53 on selected hallmarks of leukemia, particularly metabolic rewiring and immune evasion, the clinical importance of TP53 mutations; and the current progress in the development of preclinical and clinical therapeutic strategies to treat TP53- mutated disease. [ABSTRACT FROM AUTHOR]

Clustered DNA damage, when multiple lesions are generated in close proximity, has various biological consequences, including cell death, chromosome aberrations, and mutations. It is generally perceived as a hallmark of ionizing radiation. The enhanced mutagenic potential of lesions within a cluster has been suggested to result, at least in part, from the selection of the strand with the mutagenic lesion as the preferred template strand, and that this process is relevant to the tolerance of persistent single-strand breaks generated during an attempted repair. Using a plasmid-based assay in Escherichia coli, we examined how the strand bias is affected in mutant strains deficient in different DNA polymerase I activities. Our study revealed that the strand-displacement and 5′-flap endonuclease activities are required for this process, while 3′-to-5′ exonuclease activity is not. We also found the strand template that the mutagenic lesion was located on, whether lagging or leading, had no effect on this strand bias. Our results imply that an unknown pathway operates to repair/tolerate the single-strand break generated at a bi-stranded clustered damage site, and that there exist different backup pathways, depending on which DNA polymerase I activity is compromised. [ABSTRACT FROM AUTHOR]

Background: Chromosome 7 has regions enriched with low copy repeats (LCRs), which increase the likelihood of chromosomal microdeletion disorders. Documented microdeletion disorders on chromosome 7 include both well-known Williams syndrome and more rare cases. It is noteworthy that most cases of various microdeletions are characterized by phenotypic signs of neuropsychological developmental disorders, which, however, have a different genetic origin. The localization of the microdeletions, the genes included in the region, as well as the structural features of the sequences of these genes have a cumulative influence on the phenotypic characteristics of the individuals for each specific case and the severity of the manifestations of disorders. The consideration of these features and their detailed analysis is important for a correct and comprehensive assessment of the disease. Results: The article describes a clinical case of 7p22.3 microdeletion in a patient with congenital heart defect and neurological abnormalities - epilepsy, combined with moderate mental and motor developmental delay. Conclusions: Through detailed genetic analyses, we are improving the clinical description of the rare 7p22.3 microdeletion and thus creating a basis for future genetic counseling and research into targeted therapies. [ABSTRACT FROM AUTHOR]

Background and purpose: Cone beam computed tomography (CBCT) is routinely used in radiotherapy to localize target volume. The aim of our study was to determine the biological effects of CBCT dose compared to subsequent therapeutic dose by using in vitro chromosome dosimetry. Materials and methods: Peripheral blood samples from five healthy volunteers were irradiated in two phantoms (water filled in-house made cylindrical, and Pure Image CTDI phantoms) with 6 MV FFF X-ray photons, the dose rate was 800 MU/min and the absorbed doses ranged from 0.5 to 8 Gy. Irradiation was performed with a 6 MV linear accelerator (LINAC) to generate a dose–response calibration curve. In the first part of the investigation, 1–5 CBCT imaging was used, in the second, only 2 Gy doses were delivered with a LINAC, and then, in the third part, a combination of CBCT and 2 Gy irradiation was performed mimicking online adapted radiotherapy treatment. Metaphases were prepared from lymphocyte cultures, using standard cytogenetic techniques, and chromosomal aberrations were evaluated. Estimate doses were calculated from chromosome aberrations using dose–response curves. Results: Samples exposed to X-ray from CBCT imaging prior to treatment exhibited higher chromosomal aberrations and Estimate dose than the 2 Gy therapeutic (real) dose, and the magnitude of the increase depended on the number of CBCTs: 1–5 CBCT corresponded to 0.04–0.92 Gy, 1 CBCT + 2 Gy to 2.32 Gy, and 5 CBCTs + 2 Gy to 3.5 Gy. Conclusion: The estimated dose based on chromosomal aberrations is 24.8% higher than the physical dose, for the combination of 3 CBCTs and the therapeutic 2 Gy dose, which should be taken into account when calculating the total therapeutic dose that could increase the risk of a second cancer. The clinical implications of the combined radiation effect may require further investigation. [ABSTRACT FROM AUTHOR]

Chromosomal abnormalities are a common cause of human miscarriage but rarely reported in any other species. As a result, there are currently inadequate animal models available to study this condition. Horses present one potential model since mares receive intense gynecological care. This allowed us to investigate the prevalence of chromosomal copy number aberrations in 256 products of conception (POC) in a naturally occurring model of pregnancy loss (PL). Triploidy (three haploid sets of chromosomes) was the most common aberration, found in 42% of POCs following PL over the embryonic period. Over the same period, trisomies and monosomies were identified in 11.6% of POCs and subchromosomal aberrations in 4.2%. Whole and subchromosomal aberrations involved 17 autosomes, with chromosomes 3, 4, and 20 having the highest number of aberrations. Triploid fetuses had clear gross developmental anomalies of the brain. Collectively, data demonstrate that alterations in chromosome number contribute to PL similarly in women and mares, with triploidy the dominant ploidy type over the key period of organogenesis. These findings, along with highly conserved synteny between human and horse chromosomes, similar gestation lengths, and the shared single greatest risk for PL being advancing maternal age, provide strong evidence for the first animal model to truly recapitulate many key features of human miscarriage arising due to chromosomal aberrations, with shared benefits for humans and equids. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Plain Language Summary PDGFRB fusions in acute lymphoblastic leukemia (ALL) is rare. The authors identified 28 pediatric PDGFRB‐positive ALL. They analyzed the features, outcomes, and prognostic factors of this disease.This multicenter, retrospective study included 6457 pediatric patients with newly diagnosed PDGFRB fusion ALL according to the CCCG‐ALL‐2015 and CCCG‐ALL‐2020 protocols from April 2015 to April 2022 in 20 hospitals in China. Of these patients, 3451 were screened for PDGFRB fusions.Pediatric PDGFRB‐positive ALL accounted for only 0.8% of the 3451 cases tested for PDGFRB. These patients included 21 males and seven females and 24 B‐ALL and 4 T‐ALL; the median age was 10 years; and the median leukocyte count was 29.8 × 109/L at baseline. Only one patient had eosinophilia. Three patients had an IKZF1 deletion, three had chromosome 5q31‐33 abnormalities, and one suffered from a complex karyotype. The 3‐year event‐free survival (EFS), overall survival (OS), and cumulative incidence of relapse (CIR) were 33.1%, 65.5%, and 32.1%, respectively, with a median follow‐up of 25.5 months. Twenty patients were treated with chemotherapy plus tyrosine‐kinase inhibitors (TKIs) and eight were treated without TKI. Complete remission (CR) rates of them were 90.0% and 63.6%, respectively, but no differences in EFS, OS, or CIR. Univariate analyses showed patients with IKZF1 deletion or measurable residual disease (MRD) ≥0.01% after induction had inferior outcomes (p < .05).Pediatric PDGFRB‐positive ALL has a poor outcome associated with high‐risk features. Chemotherapy plus TKIs can improve the CR rate, providing an opportunity for lower MRD levels and transplantation. MRD ≥0.01% was a powerful adverse prognostic factor, and stratified treatment based on MRD may improve survival for these patients. Pediatric acute lymphoblastic leukemia patients with PDGFRB fusions are associated with high‐risk clinical features such as older age, high white blood cell count at diagnosis, high measurable residual disease after induction therapy, and increased risk of leukemia relapse. Chemotherapy plus tyrosine‐kinase inhibitors can improve the complete remission rate and provide an opportunity for lower measurable residual disease (MRD) levels and transplantation for pediatric PDGFRB‐positive acute lymphoblastic leukemia (ALL) patients. The MRD level was also a powerful prognostic factor for pediatric PDGFRB‐positive ALL patients. Pediatric acute lymphoblastic leukemia patients with PDGFRB fusions are associated with high‐risk clinical features such as older age, high white blood cell count at diagnosis, high measurable residual disease after induction therapy, and increased risk of leukemia relapse.Chemotherapy plus tyrosine‐kinase inhibitors can improve the complete remission rate and provide an opportunity for lower measurable residual disease (MRD) levels and transplantation for pediatric PDGFRB‐positive acute lymphoblastic leukemia (ALL) patients.The MRD level was also a powerful prognostic factor for pediatric PDGFRB‐positive ALL patients. [ABSTRACT FROM AUTHOR]

Male infertility affects approximately 17% of all men and represents a complex disorder in which not only semen parameters such as sperm motility, morphology, and number of sperm are highly variable, but also testicular phenotypes range from normal spermatogenesis to complete absence of germ cells. Genetic factors significantly contribute to the disease but chromosomal aberrations, mostly Klinefelter syndrome, and microdeletions of the Y‐chromosome have remained the only diagnostically and clinically considered genetic causes. Monogenic causes remain understudied and, thus, often unidentified, leaving the majority of the male factor couple infertility pathomechanistically unexplained. This has been changing mostly because of the introduction of exome sequencing that allows the analysis of multiple genes in large patient cohorts. As a result, pathogenic variants in single genes have been associated with non‐syndromic forms of all aetiologic sub‐categories in the last decade.This review highlights the contribution of exome sequencing to the identification of novel disease genes for isolated (non‐syndromic) male infertility by presenting the results of a comprehensive literature search. Both, reduced sperm count in azoospermic and oligozoospermic patients, and impaired sperm motility and/or morphology, in asthenozoospermic and/or teratozoospermic patients are highly heterogeneous diseases with well over 100 different candidate genes described for each entity. Applying the standardized evaluation criteria of the ClinGen gene curation working group, 70 genes with at least moderate evidence to contribute to the disease are highlighted. The implementation of these valid disease genes in clinical exome sequencing is important to increase the diagnostic yield in male infertility and, thus, improve clinical decision‐making and appropriate genetic counseling.Future advances in androgenetics will continue to depend on large‐scale exome and genome sequencing studies of comprehensive international patient cohorts, which are the most promising approaches to identify additional disease genes and provide reliable data on the gene–disease relationship. [ABSTRACT FROM AUTHOR]

Objective: To explore the association between the concentration of maternal serum biomarkers and the risk of fetal carrying chromosome copy number variants (CNVs). Methods: Pregnant women identified as high risk in the second-trimester serological triple screening and underwent traditional amniotic fluid karyotype analysis, along with comparative genomic hybridization array (aCGH)/copy number variation sequencing (CNV-seq), were included in the study. We divided the concentration of serum biomarkers, free beta-human chorionic gonadotropin (fβ-hCG), alpha fetoprotein (AFP) and unconjugated estriol (uE3), into three levels: abnormally low, normal and abnormally high. The prevalence of abnormally low, normal and abnormally high serum fβ-hCG, AFP and uE3 levels in pregnant women with aberrant aCGH/CNV-seq results and normal controls was calculated. Results: Among the 2877 cases with high risk in the second-trimester serological triple screening, there were 98 chromosome abnormalities revealed by karyotype analysis, while 209 abnormalities were detected by aCGH/CNVseq (P＜0.001). The carrying rate of aberrant CNVs increased significantly when the maternal serum uE3 level was less than 0.4 multiple of median (MoM) of corresponding gestational weeks compared to normal controls, while the carrying rate of aberrant CNVs decreased significantly when the maternal serum fβ-hCG level was greater than 2.5 MoM compared to normal controls. No significant difference was found in the AFP group. Conclusion: Low serum uE3 level (<0.4 MoM) was associated with an increased risk of aberrant CNVs. [ABSTRACT FROM AUTHOR]

Chromosome inversions are of unique importance in the evolution of genomes and species because when heterozygous with a standard arrangement chromosome, they suppress meiotic crossovers within the inversion. In Drosophila species, heterozygous inversions also cause the interchromosomal effect, whereby the presence of a heterozygous inversion induces a dramatic increase in crossover frequencies in the remainder of the genome within a single meiosis. To date, the interchromosomal effect has been studied exclusively in species that also have high frequencies of inversions in wild populations. We took advantage of a recently developed approach for generating inversions in Drosophila simulans , a species that does not have inversions in wild populations, to ask if there is an interchromosomal effect. We used the existing chromosome 3R balancer and generated a new chromosome 2L balancer to assay for the interchromosomal effect genetically and cytologically. We found no evidence of an interchromosomal effect in D. simulans. To gain insights into the underlying mechanistic reasons, we qualitatively analyzed the relationship between meiotic double-stranded break (DSB) formation and synaptonemal complex (SC) assembly. We found that the SC is assembled prior to DSB formation as in D. melanogaster ; however, we show that the SC is assembled prior to localization of the oocyte determination factor Orb, whereas in D. melanogaster , SC formation does not begin until the Orb is localized. Together, our data show no evidence that heterozygous inversions in D. simulans induce an interchromosomal effect and that there are differences in the developmental programming of the early stages of meiosis. [ABSTRACT FROM AUTHOR]

Deficiency of Adenosine Deaminase 2 (DADA2) is a systemic disorder that is inherited in an autosomal recessive manner. Initially identified as a monogenic form of systemic vasculitis that mirrors polyarteritis nodosa (PAN), DADA2 is attributed to biallelic pathogenic variants in the adenosine deaminase 2 gene (ADA2; formerly known as CECR1) on chromosome 22q11. DADA2 presents with variable symptoms that can manifest as vasculitis, immune dysfunction, or hematological abnormalities. The primary disease phenotypes consist of polyarteritis nodosa (PAN)-like vasculitis, Diamond-Blackfan anemia (DBA)-like hematologic findings, and immunodeficiency. The vasculitic condition often manifests through severe ischemic or hemorrhagic strokes that can be life-threatening. To confirm the diagnosis of DADA2, it is imperative to analyze the ADA2 gene and measure low or unnoticeable ADA2 activity in plasma or serum. The use of anti-tumor necrosis factor agents has proven to be efficacious in treating patients with an inflammatory phenotype. Hematopoietic stem cell transplantation (HSCT) stands out as a promising treatment alternative for patients presenting with predominant hematologic or immunologic manifestations. [ABSTRACT FROM AUTHOR]