Aneuploidy describes a numerical change in an organism’s chromosomes, resulting in cells that have either too many or too few chromosomes compared to the normal set. Humans typically have 46 chromosomes, arranged in 23 pairs. A cell is considered aneuploid if it contains 45 or 47 chromosomes, or other non-multiples of the haploid set. This genetic imbalance caused by an extra or missing chromosome is the most common known cause of developmental disorders and is responsible for a significant majority of miscarriages and pregnancy losses.
The Genetics of Aneuploidy
The underlying cause of aneuploidy is a failure in cellular division known as nondisjunction, which occurs during the creation of egg or sperm cells (gametes). Gametes are produced through meiosis, a specialized process where the chromosome number is reduced by half. Nondisjunction is the error in which homologous chromosomes or sister chromatids do not separate properly, leading to gametes with an incorrect number of chromosomes.
Nondisjunction can occur in two distinct phases of meiosis. If the error happens during Meiosis I, homologous chromosome pairs fail to separate, resulting in gametes that either have an extra chromosome or are missing one. Errors during Meiosis II involve the sister chromatids failing to separate, producing two normal gametes, one with an extra chromosome, and one with a missing chromosome. Errors during Meiosis I are statistically a more frequent source of aneuploidy.
The resulting gamete, with its abnormal chromosome count, then fuses with a normal gamete to form a zygote. If the resulting embryo has an extra chromosome, the condition is termed a trisomy, meaning three copies of a specific chromosome are present instead of the usual two. Conversely, if the embryo is missing a chromosome, the condition is called a monosomy, where only a single copy of that chromosome exists. Both trisomy and monosomy lead to a severe imbalance in gene dosage, which is why most aneuploidies are incompatible with life and often result in miscarriage.
Identifying Common Aneuploidies
While most aneuploidies result in early pregnancy loss, certain imbalances involving smaller chromosomes or sex chromosomes can result in viable births. The most frequently encountered autosomal aneuploidy among live births is Trisomy 21, commonly known as Down Syndrome, which involves an extra copy of chromosome 21. Individuals with Trisomy 21 often present with distinct physical features, developmental delays, and an increased incidence of medical conditions, such as congenital heart defects.
Two other autosomal trisomies that result in live births are Trisomy 18 (Edwards Syndrome) and Trisomy 13 (Patau Syndrome). Trisomy 18 is characterized by severe developmental abnormalities, leading to a significantly reduced lifespan, with most affected infants not surviving beyond their first year. Trisomy 13 is associated with profound intellectual disability and severe physical defects, including structural brain abnormalities.
Sex chromosome aneuploidies often have less severe health consequences than autosomal trisomies. For example, Klinefelter Syndrome results from an extra X chromosome in males (XXY), which can lead to reduced fertility, taller stature, and subtle learning or speech differences. Turner Syndrome, which affects females, is a monosomy resulting from a missing or partially missing X chromosome (XO), frequently causing short stature, ovarian dysfunction, and specific heart or kidney abnormalities.
Factors Influencing Aneuploidy Risk
The single most well-established factor influencing the risk of aneuploidy is advanced maternal age. A woman is born with all the eggs she will ever have, and these oocytes are arrested in the first meiotic division for decades until ovulation occurs. This prolonged arrest leads to a deterioration of the cellular machinery responsible for accurate chromosome separation.
Over time, components responsible for accurate chromosome separation become less effective. This degradation increases the likelihood of nondisjunction when the egg finally completes meiosis. The effect is pronounced, with the risk of producing an embryo with aneuploidy escalating significantly after a maternal age of 35, and increasing exponentially after 40.
Paternal age is also considered a factor, though its contribution to aneuploidy risk is less substantial than maternal age. While sperm are continuously produced, errors in meiosis can still occur in older fathers, potentially contributing to some cases of Trisomy 21 and certain sex chromosome aneuploidies. Environmental exposures or genetic predispositions in either parent are also being studied as potential contributors to segregation errors.
Methods for Detection and Screening
Medical professionals utilize a variety of methods to assess the risk of fetal aneuploidy during pregnancy, which are broadly categorized as either screening or diagnostic tests. Screening tests are non-invasive and provide a risk assessment, while diagnostic tests are invasive procedures that offer a definitive confirmation of the presence or absence of a condition.
One of the most widely used screening methods is Non-Invasive Prenatal Testing (NIPT), which can be performed as early as 10 weeks of gestation. NIPT analyzes small fragments of cell-free fetal DNA that circulate in the mother’s bloodstream, allowing for accurate risk assessment of the most common trisomies, including Trisomy 21, 18, and 13. Traditional screening, which combines a first-trimester ultrasound for nuchal translucency measurement with maternal serum blood markers, also provides a risk score but is less sensitive than NIPT.
For a definitive diagnosis, invasive procedures such as Chorionic Villus Sampling (CVS) and amniocentesis are performed. CVS involves sampling tissue from the placenta, typically between 10 and 13 weeks, while amniocentesis involves collecting amniotic fluid, usually after 15 weeks. Since these tests analyze fetal cells directly, they provide a karyotype, offering a conclusive answer regarding the presence of an aneuploidy. Because these diagnostic procedures carry a measurable risk of miscarriage, they are typically reserved for cases where screening tests indicate a high risk or when definitive information is needed.