Journal of Rare Disorders: Diagnosis & Therapy

Description

With increasing maternal age comes an increase in the incidence of trisomy and egg aneuploidy. Due to the fact that chromosomal abnormalities in mammalian eggs are caused by a variety of factors, it is unclear to what extent individual treatments can delay the "maternal age effect.” The ability to precisely segregate chromosomes and produce euploid eggs is one important aspect of the physiological aging of oocytes, which we propose is determined by ovulation frequency. Using successive pregnancies, hormonal contraception, and a pre-pubertal knockout mouse model, ovulations were reduced, and the effects on chromosome segregation and egg ploidy were examined to test this hypothesis. We demonstrate that each intervention reduces chromosomal abnormalities in aged eggs, indicating that ovulation reduction slows the aging of oocytes. The retention of chromosomal Rec8-cohesin, which helps to maintain sister chromatid cohesion during meiosis, may partially account for the protective effect. In addition, long-lived oocytes' extruded loop sizes increased when single-nucleus Hi-C (snHi-C) was used to measure the 3D chromatin structure. Rec8 can be cleaved artificially to produce larger extruded loops, indicating that cohesin complexes that maintain cohesion prevent loop extrusion. These results suggest that suppressing ovulation protects against Rec8 loss, promoting the production of euploid eggs and maintaining sister chromatid cohesion and 3D chromatin structure. We conclude that mice can delay the maternal age effect.

Miscarriage Aneuploidies

This study suggests that at an advanced maternal age, long-term ovulation-suppressing conditions may reduce the risk of aneuploid pregnancies. Chromosome abnormalities that result in Disorders of Sex Development (DSD) are rarely diagnosed in dogs. This report focuses on five DSD cases in which the dogs' karyotypes were abnormal. Owners recognized all of the animals as females, but these dogs had numerous reproductive defects. In four dogs, abnormalities in the vulva and urethral orifice, abnormal development of the labia, and abnormal external genitalia like an enlarged clitoris were among these. Three dogs' gonad histology was examined, and ovotestis with calcification in ovarian follicles, inactive testes, and the presence of an ovary were identified. The majority of miscarriages are brought on by chromosomal abnormalities in the embryo. In clinical practice, it is necessary to have an inexpensive, accurate, and quick method for chromosome analysis after a miscarriage. As a result, an HLPA-based high-throughput method for miscarriage aneuploidies and copy number variations detection was developed. A total of 1060 miscarriage cases were evaluated. Chromosomal Microarray Analysis (CMA) and Quantitative Fluorescence (QF)-PCR/HLPA were performed simultaneously on each specimen. Both methods were used to successfully analyze all 1060 samples; 1. 7% (18/1060) of these samples were found to be significantly contaminated with maternal cells. The sensitivity and specificity of QF-PCR/HLPA in identifying total pathogenic chromosomal abnormalities were 98. 9% and 100%, respectively, when compared to CMA results. In addition, there was no significant difference in the overall prevalence of chromosomal abnormalities between spontaneous abortions and recurrent miscarriages. In conclusion, compared to CMA, QF-PCR/HLPA identified chromosomal abnormalities more quickly, accurately, and for less money than CMA. QF-PCR/HLPA may be a promising strategy for routine genetic testing in clinical miscarriage due to its simplicity, accuracy, and affordability. According to ELN 2017, the patient's KMT2A gene rearrangement at the time of diagnosis of AML places them in the group with adverse cytogenetic risk.

AML is one of many hematooncological diseases in which abnormalities in other parts of chromosome 11 are found. However, their significance for OS, CR rate, and outcome remains unknown. The primary objective of this study was to examine the effects of chromosome 11 abnormalities on patients' outcomes in AML patients who did not have a KMT2A gene rearrangement. For the purpose of stratifying patients with various myeloid neoplasms, cytogenetic analysis is essential. In cases of Myelo-Dysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML), whole-genome sequencing may be used in place of cytogenetic analysis. We looked into the possibility of using liquid biopsy and Next Generation Sequencing (NGS) to detect chromosomal structural abnormalities or Copy Number Variation (CNV) in patients with myeloid neoplasms in light of the growing use of liquid biopsy in the diagnosis and monitoring of various types of neoplasms. For the purpose of determining the chromosomal structural abnormalities in cell-free DNA (cfDNA) in patients with myeloid neoplasms, we utilized targeted sequencing for a practical approach, to capture Single Nucleotide Variants (SNV), and to achieve sufficient depth in sequencing. Mercury (Hg) is one of the most harmful pollutants for the environment, particularly when methylated to make methylmercury (MeHg). DNA repair is affected, oxidative stress is increased, and cancer predisposes to MeHg. Neurotoxicity from MeHg is well-known, but cardiovascular effects from MeHg were recently discovered.

Liver Lipid Peroxidation

After MeHg-chronic exposure (20 mg/L in drinking water) in C57BL/6J wild-type and APOE knockout (ko) mice, the latter of which developed spontaneous dyslipidemia, circulating lipids, oxidative stress, and genotoxicity were examined in this study. Four groups of experimental mice were selected: both APOE ko mice and wild-type mice were found to be unaffected by either MeHg or MeHg. The triglyceride, Total Cholesterol (TC), HDL, and LDL levels in the plasma were examined. Xeroderma pigmentosum complementation groups A, C, D, and G (XPA, XPC, XPD, and XPG), X-ray Repair Cross-Complementing protein 1 (XRCC1), and telomerase reverse transcriptase gene expression and liver lipid peroxidation were measured. Fur Hg levels proved that MeHg intoxication was ongoing. MeHg exposure raises TC levels in both APOE ko and wild-type mice. Only the MeHg-challenged APOE ko mice showed an increase in HDL and LDL cholesterol levels. MeHg raised lipid peroxidation in the liver regardless of genetic background. TERT expression was higher in the APOE ko group than in any other group of mice. Despite MeHg intoxication, APOE deficiency increases XPA expression. Furthermore, despite the absence of APOE, MeHg-intoxicated mice displayed a greater number of cytogenetic abnormalities. Even at a young age, more research is needed to understand how DNA repair pathways, MeHg poisoning, and circulating lipids interact with one another.  These interactions are likely crucial to cell senescence and the risk of developing chronic diseases in later life. There is conflicting evidence regarding whether additional cytogenetic abnormalities in addition to the standard Philadelphia (Ph) translocation increase the likelihood of disease progression after CML diagnosis. Diagnostic karyotypes were available in 763 of the 814 patients recruited for the SPIRIT2 trial in the United Kingdom, which compared dasatinib 100 mg daily with imatinib 400 mg daily. 27 of these had ACAs in one or both of the original four major route groups (trisomy 8 or 19, iso17q, or a second Ph) or the five additional lesions that had just been described (trisomy 21, 3q26. 2, monosomy 7/7q, 11q23, or complex karyotypes), and their progression rate was significantly higher than that of patients who did not have one of these ACAs (22. 2 percent; 2. 2 percent;P < . 001). PFS (progression-free survival) was lower in ACA patients. Long-term survival scores from the Sokal or European Treatment and Outcome Study did not correlate with the presence of ACAs. PFS was correlated with higher Sokal and ELTS scores and the presence of ACAs, according to univariate analysis; however, only ACAs and high-risk ELTS scores were correlated with poorer FFP. Both the Sokal/ELTS score and the ACAs were found to be significant independent factors in multivariable models for PFS, but only the ELTS score and the ACAs were found to be significant independent factors in FFP. The data back up the idea that some ACAs are better predictors of disease progression than Sokal or ELTS scores alone.