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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
The main cause of chromosomal structural abnormality is double-stranded DNA breakage. DNA breakage occurs as a natural feature of meiosis, but can also be triggered by ionizing radiation. Broken ends of DNA are rapidly repaired by specific enzymes. Abnormal repair generates structural abnormalities including translocations, deletions, duplications and inversions of DNA segments. Translocations represent a transfer of DNA between two chromosomes. This exchange does not necessarily result in loss of DNA, so an individual carrier may remain healthy. However, chromosome translocations can interfere with meiosis such that offspring cells may receive a partial trisomy or monosomy. Deletions result in a loss of genetic material, often spanning many genes. Their effects can be severe, resulting in congenital malformation. Duplications of a DNA stretch are generally less harmful than deletions. Introduction of two separate double-stranded breaks can generate an inversion if the chromosomal fragment is reinserted in a back-to-front orientation. Although no DNA is lost or gained in this process, inversions can obstruct chromosome pairing during meiosis.
Prenatal Diagnosis and Screening for Aneuploidy
Published in Vincenzo Berghella, Obstetric Evidence Based Guidelines, 2022
Sarah Harris, Angie Jelin, Neeta Vora
Fluorescent in situ hybridization (FISH) allows for the rapid and accurate detection of trisomies 21, 18, and 13, as well as sex chromosome aneuploidy and triploidy. These common aneuploidies account for 80% of clinically significant chromosome conditions detected prenatally [46]. In the event of an abnormal FISH result, confirmatory testing should be completed using a conventional karyotype to determine if a chromosomal translocation is present. If FISH results are normal, then additional testing with conventional karyotype or chromosomal microarray (CMA) analysis should be considered to rule out less common aneuploidies or to identify smaller deletions or duplications that would be missed using FISH alone.
Basic genetics and patterns of inheritance
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
The second type of screening includes testing of targeted ethnic or racial populations to identify carriers of genetic disease. Examples are cystic fibrosis in Caucasians, Tay–Sachs disease in Ashkenazi Jews, and hemoglobinopathies in African-Americans (10). On a smaller scale, genetic screening can involve karyotype analysis on family members at risk for having a chromosome translocation. Carrier testing is also available for women who are at risk to be carriers for X-linked disorders such as Duchenne muscular dystrophy or Fragile X syndrome. This type of population screening will not affect the health of the carrier, but will have a significant impact on reproductive choices for the family. It is essential that appropriate genetic counseling accompany the information given regarding carrier status.
Genetic variations as molecular diagnostic factors for idiopathic male infertility: current knowledge and future perspectives
Published in Expert Review of Molecular Diagnostics, 2021
Mohammad Karimian, Leila Parvaresh, Mohaddeseh Behjati
Balanced chromosomal translocations involve the breakage of two chromosomes and abnormal repair of chromosomal fragments resulting in the transfer of genetic material from one chromosome to another without loss of any genetic material. In vast majority of cases, carriers of balanced translocations are phenotypically normal, unless one of the breakpoints at the site of translocation disrupts an important gene. Chromosomal translocation, while phenotypically normal, may experience fertility loss, miscarriage, or birth defects. Normal meiotic segregation of these translocations in gametes can lead to duplication or deletion of chromosomal regions involved in translocation [171]. Like chromosomal translocations, inversions can lead to infertility, miscarriage, and birth defects. During meiosis, chromosomes are forced to form specialized structures, so that homologous chromosomes can be paired. Chromosomal inversions can affect these specialized structures. Research on the production of unbalanced gametes in balanced inversion carriers has been done to a much lesser extent than translocations. However, a handful of studies have reported an unbalanced sperm range of 1–54% [172–174].
Cytogenetic and molecular genetic methods for chromosomal translocations detection with reference to the KMT2A/MLL gene
Published in Critical Reviews in Clinical Laboratory Sciences, 2021
Nikolai Lomov, Elena Zerkalenkova, Svetlana Lebedeva, Vladimir Viushkov, Mikhail A. Rubtsov
This review summarizes the current methods for detection of chromosomal translocations, with KMT2A-associated AL as an example. These methods differ in their applicability, required time, and cost (Table 1). Routine clinical diagnosis of AL is usually limited to karyotyping and FISH with a standard set of probes (e.g. KMT2A BA probes) and provides only gross information regarding chromosomal abnormalities and the presence of well-known chromosomal translocations. Routine karyotyping can be complemented by more informative, multicolor FISH methods: M-BAND, M-FISH, and SKY. These methods are suitable for the identification of complex chromosomal rearrangements and have better resolution than conventional karyotyping. More profound analysis, including determination of the translocation partner locus and the exact location of a breakpoint, is essential, as it influences the estimation of prognosis and selection of therapy protocols. To this aim, PCR-based approaches, such as LDI-PCR or NGS, may be the methods of choice. These methods allow the identification of new partner genes that have not been previously observed in translocations. Due to the high heterogeneity of KMT2A-rearrangements, a whole variety of methods should be applied. A representative scheme of chromosomal translocation detection integrating all mentioned methods is shown in Figure 8.
Chronic low dose exposure of hospital workers to ionizing radiation leads to increased micronuclei frequency and reduced antioxidants in their peripheral blood lymphocytes
Published in International Journal of Radiation Biology, 2019
Zothan Siama, Mary Zosang-zuali, Annie Vanlalruati, Ganesh Chandra Jagetia, Kham Suan Pau, Nachimuthu Senthil Kumar
The MN assay has been used as a quantitative indicator of X-ray induced chromosome damage in several studies, both in vitro and in vivo (Ramalho et al. 1998; Maffei et al. 2002; Joseph et al. 2004; Ropolo et al. 2012; Koyama et al. 2016). Our results indicate that the mean MNBNC frequency was significantly higher in exposed workers than in controls irrespective of their demographic characteristics. Our findings are in agreement with other studies on occupational workers from China, Korea and Romania population, where a higher MN frequency has been reported after exposure to chronic low doses of ionizing radiation (An and Kim 2002; Mihalache et al. 2007; Sahin et al. 2009; Eken et al. 2010; Zakeri and Hirobe 2010; Sakly et al. 2013; Qian et al. 2016; Gharibdousty et al. 2017; Lusiyanti et al. 2017). The radiological technicians also showed an increase in chromosome translocations in a US study (Sigurdson et al. 2008). In contrast, some studies did not find any increase in the MN frequency in the exposed group as compared to controls, which may be due to several other confounding factors (Demirel et al. 1997; Thierens et al. 2000). Our results further indicated a strong association between MNBNC frequency and the duration of working with IR (X-rays), number of patients handled by a radiology worker per day and the age of the exposed group (Table 4).