A chromosomal disorder results from an abnormal number of chromosomes within a cell. Human cells typically contain 46 chromosomes, arranged in 23 pairs. Too many or too few copies of a chromosome disrupt the genetic balance necessary for proper development. The mechanical error responsible for these numerical errors is nondisjunction, a failure in cell division that leads to reproductive cells, or gametes, with an incorrect chromosome count.
Defining Nondisjunction
Nondisjunction is the failure of chromosomes to separate correctly during meiosis, the process that forms sperm and egg cells. Normally, replicated chromosomes or their halves (chromatids) are pulled to opposite ends of the cell, ensuring each new cell receives the correct genetic material. When nondisjunction occurs, a pair of chromosomes or chromatids fails to pull apart, causing both to migrate to one pole of the dividing cell.
This error results in gametes with an abnormal number of chromosomes, a condition termed aneuploidy. A gamete receiving an extra copy is described as having \(n+1\) chromosomes, while one missing a copy is described as having \(n-1\) chromosomes. When an aneuploid gamete fuses with a normal gamete during fertilization, the resulting embryo has an overall imbalance. If the embryo has three copies of a chromosome, it is known as a trisomy; if it has only one copy, it is a monosomy.
How Errors Occur During Meiosis
Nondisjunction can occur at two distinct points during the two-step meiotic process, and the timing of the error dictates the ultimate fate of the resulting reproductive cells.
Meiosis I Nondisjunction
Nondisjunction can occur during Meiosis I, the first division where homologous chromosomes—the paired copies inherited from each parent—are meant to separate. In this error, the homologous chromosomes fail to pull apart and move together into a single daughter cell. Since the initial division failed, the two secondary cells formed are immediately abnormal. When these cells proceed through Meiosis II, they produce four final gametes, all of which are aneuploid: two \(n+1\) and two \(n-1\).
Meiosis II Nondisjunction
Alternatively, the error can occur during the second division, known as Meiosis II nondisjunction. Here, the first meiotic division proceeds normally, but the sister chromatids fail to separate in one or both secondary cells. If the error occurs in only one secondary cell, the final four gametes have a different outcome. Two gametes will be normal (\(n\)), and the other two will be aneuploid: one \(n+1\) and one \(n-1\). Therefore, a Meiosis II error results in a 50% chance of producing a normal gamete, unlike a Meiosis I error which results in only abnormal gametes.
The Resulting Aneuploidy and Chromosomal Conditions
When an abnormal gamete (\(n+1\) or \(n-1\)) is fertilized by a normal gamete (\(n\)), the resulting single-celled embryo, or zygote, is aneuploid. A fusion involving an \(n+1\) gamete results in a trisomic zygote (2n+1), meaning it carries 47 total chromosomes with three copies of a specific chromosome. Conversely, an \(n-1\) gamete results in a monosomic zygote (2n-1), carrying 45 total chromosomes with only one copy of a specific chromosome.
Monosomies, the loss of an entire autosome (non-sex chromosome), are almost universally lethal, resulting in very early miscarriage because the complete absence of genetic information is too disruptive for development. The only monosomy compatible with life is Monosomy X (45, X), which causes Turner Syndrome in females, characterized by short stature and ovarian dysgenesis. In contrast, while most autosomal trisomies also lead to miscarriage, a few are known to allow for live birth.
The most common viable autosomal trisomy is Down Syndrome, caused by an extra copy of chromosome 21 (Trisomy 21). This condition occurs in approximately 1 in 700 to 1,000 live births and is characterized by distinct facial features, intellectual disability, and often congenital heart defects. Two other less common but recognized autosomal trisomies are Edwards Syndrome (Trisomy 18) and Patau Syndrome (Trisomy 13).
Edwards Syndrome is the second most common, associated with severe developmental delays and multiple congenital malformations, resulting in a very short life expectancy. Patau Syndrome (Trisomy 13) is associated with profound physical abnormalities, including cleft lip, heart defects, and brain anomalies, with most affected infants surviving only a few days or weeks. Aneuploidies can also involve sex chromosomes, such as Klinefelter Syndrome (47, XXY), where a male has an extra X chromosome, often leading to fertility issues and taller stature.
Factors Increasing the Risk of Nondisjunction
The strongest factor associated with an increased frequency of nondisjunction is advanced maternal age. A woman is born with all her primary oocytes, which remain suspended in Meiosis I for decades until ovulation. The risk of nondisjunction begins to rise noticeably after age 35 and increases exponentially thereafter.
This phenomenon relates to the prolonged suspension of the meiotic process, which subjects cellular machinery and chromosome connections to potential degradation. Structures that hold homologous chromosomes together, called chiasmata, and the meiotic spindle fibers may weaken over time. This “wear and tear” makes the precise segregation of chromosomes more prone to error when meiosis finally resumes. Advanced paternal age is also a minor contributing factor.