aneuploidy

Aneuploidy results from errors in chromosome segregation during meiosis I or II (nondisjunction) or mitosis, leading to gametes or cells with an extra or missing chromosome. The most common mechanism is nondisjunction during meiosis I, where homologous chromosomes fail to separate properly, though meiosis II errors (sister chromatid nondisjunction) also occur. Maternal age is the strongest risk factor, particularly for trisomy 21, due to prolonged arrest of oocytes in meiosis I increasing the chance of spindle apparatus failure. Clinically significant aneuploidies include: Trisomy 21 (Down syndrome) - most common autosomal trisomy, associated with intellectual disability, characteristic facies, congenital heart defects (endocardial cushion defects), duodenal atresia, and increased risk of Alzheimer disease and ALL. Trisomy 18 (Edwards syndrome) - rocker-bottom feet, clenched hands with overlapping fingers, micrognathia, severe intellectual disability, congenital heart defects; most die within the first year. Trisomy 13 (Patau syndrome) - cleft lip/palate, polydactyly, microphthalmia, holoprosencephaly, cutis aplasia. Monosomy X (Turner syndrome, 45,X) - short stature, webbed neck, primary amenorrhea, streak ovaries, horseshoe kidney, bicuspid aortic valve, and coarctation of the aorta. Klinefelter syndrome (47,XXY) - tall stature, testicular atrophy, gynecomastia, infertility due to hypogonadism. Screening for aneuploidy involves first-trimester combined screening (nuchal translucency, PAPP-A, beta-hCG), quad screen in the second trimester, and cell-free fetal DNA testing (NIPT). Definitive diagnosis requires karyotype analysis via chorionic villus sampling or amniocentesis. Aneuploidy is a major cause of first-trimester spontaneous abortions.