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Aneuploidy in Human Oocytes and Preimplantation Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
After 30 years of widely held belief that humans had 48 chromosomes, the refinement of karyotyping techniques in the 1950s facilitated the discovery that humans have 46 chromosomes, including the XY sex chromosomes (1). Using improved cytogenetic techniques, Jacobs and Strong (1959) reported that Klinefelter Syndrome in males was caused by an extra X chromosome (2). In the same year, Jejeune, Gauthier, and Turpin (3,4) and the Jacobs group (5) independently discovered that Down Syndrome was caused by an extra chromosome 21. Ford and colleagues (6) found that Turner Syndrome was caused by the loss of an X chromosome (45,X) in females and also reported the first mosaic individual (XXY/XX)(7). These studies reported in 1959 led to an explosion in the investigations into aneuploidy (8–12) and initiated epidemiological and extensive cohort studies of both spontaneous miscarriages as well as live births (Figure 8.1). Of spontaneous miscarriages, nearly 50% are chromosomally abnormal, mainly due to aneuploidy (one in three), but triploid conceptions are also common (13). To date, the most comprehensive cohort study is the US National Down Syndrome Project, which was initiated by Terry Hassold and Stephanie Sherman (14).
Basic genetics and patterns of inheritance
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Klinefelter syndrome is caused by the presence of an extra X chromosome in a phenotypic male (47,XXY) and occurs in approximately 1 in 500 to 1 in 1000 males. If Klinefelter syndrome is detected prenatally, it is usually by chance, when an amniocentesis is being done for other reasons. There are no expected fetal anomalies in Klinefelter syndrome and most cases are not diagnosed in infancy. The diagnosis may be suspected in a boy with tall thin body habitus and mild learning disabilities. Testicular size is usually normal in prepubertal boys. However, boys with Klinefelter syndrome fail to go through puberty normally and eventually have small, firm testes and relatively hypoplastic external genitalia. They are usually sterile, and the diagnosis is sometimes made in an adult infertility or urology clinic.
Aicardi Syndrome and Klinefelter Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Klinefelter syndrome, first reported by Klinefelter et al. in 1942, is a common genetic disorder that occurs in males with an extra X chromosome (XXY) instead of the usual male sex karyotype (XY). Clinically, Klinefelter syndrome is characterized by small testes (that do not produce as much testosterone as usual), delayed or incomplete puberty, gynecomastia (breast enlargement), sparse facial and body hair, azoospermia (inability to produce sperm), infertility, cryptorchidism (undescended testes), hypospadias (the opening of the urethra on the underside of the penis), micropenis (unusually small penis), tall stature, and increased risk for extragonadal germ cell tumor (GCT), breast cancer, and systemic lupus erythematosus (Table 2.1). Cytogenetically, 90% of Klinefelter syndrome patients possess non-mosaic 47,XXY karyotype (due to the aneuploidy of the sex chromosomes), 7% are mosaic (e.g., 47,XXY/46,XY), and 3% have variant (e.g., 48,XXXY or 48,XXYY) and structurally abnormal X chromosome (e.g., 47,iXq,Y) [3].
The Importance of Defining Actionability as Related to Disclosure of Secondary Findings Identified in Research
Published in The American Journal of Bioethics, 2022
Regarding this case specifically, Klinefelter syndrome is believed to be a highly underdiagnosed condition in which affected individuals have variable presentations of symptoms. Of note, although nearly two thirds of individuals with Klinefelter syndrome are likely undiagnosed, this should not equate to lack of medical implications for actionability for those in which the syndrome is identified (Davis 2015). Early diagnosis of Klinefelter syndrome may prompt evaluations for potential speech or neurodevelopmental delay, early supplemental testosterone treatment, or surgical interventions for cryptorchidism or inguinal hernia. Likewise, those diagnosed prior to puberty may be evaluated by a pediatric endocrinologist to discuss supplemental testosterone and/or other treatments to minimize gynecomastia or hypogonadism (Davis 2014). Post-puberty, individuals with Klinefelter syndrome are more likely to develop type-2 diabetes, dyslipidemia, fatty liver disease, peripheral vascular disease, and thromboembolic disease in addition to low bone density. As such, those with a diagnosis are recommended to follow with appropriate specialists to monitor and manage care.
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
Sex chromosomal abnormalities in men with Klinefelter syndrome (XXY 47) and 47 XYY syndromes are each seen in approximately 1–2 cases per 1000 live births [175]. A high percentage of men with Klinefelter syndrome are identified only when they are being evaluated for fertility. The non-mosaic form of Klinefelter syndrome accounts for about 11% of azoospermic individuals, whereas mosaic individuals are often oligospermia [176]. People who have 47XYY karyotype are fertile but seem to be more likely to be infertile compared to normal 46 XY men [177]. Due to the presence of extra sex chromosomes in both the Klinefelter and 47XYY groups, there is a theoretical risk that sex chromosomal aneuploidy will occur in at least 50% of their sperm. In 47XYY individuals, aneuploidy levels are often reported to be significantly higher than men with normal karyotype, but is often lower than those reported for Klinefelter syndrome [178]. These studies show that some aneuploid cells are able to initiate and complete meiosis, leading to the development of aneuploid gametes. However, it seems that some meiotic checkpoints are still unknown, which effectively remove a large portion of aneuploid sperm.
Revising, Correcting and Transferring Genes: Germline Editing Versus Natural Reproduction
Published in The American Journal of Bioethics, 2020
Two risks are present in all germline edits. (1) the risk to the individual that will be created, and (2) the risk to future generations as variant alleles becomes more common. While we are concerned with (1), (2) is at the forefront of this analysis, as it produces extra considerations. If (1) was the primary concern then we would be free to edit the genotype of individuals with Klinefelter syndrome, a disorder that often removes the ability of males to produce sperms (Lanfranco et al. 2004). The same embryonic edits could be made to Klinefelter individuals as healthy individuals and in this case somatic cell criteria capture everything that is important. However, the novel risk to future generations is important so we should keep the germ/somatic distinction and focus on (2). If we ignore put risks to the individual under the somatic criteria and just focus on future generations we can see the parallel to natural reproduction. What we are concerned with is introducing harmful alleles at the population level, and our aim is to minimize their occurrence.