Trisomy is a genetic condition defined by the presence of an extra copy of a specific chromosome in the body’s cells, resulting in three copies instead of the typical two. This deviation is a form of aneuploidy, an abnormal number of chromosomes. Humans typically have 23 pairs of chromosomes, totaling 46, but a full trisomy results in 47 chromosomes in each affected cell. This imbalance in genetic material affects an organism’s development and cellular function, often leading to developmental delays and characteristic physical features.
How Trisomy Occurs
The primary mechanism leading to trisomy is an error in cell division called nondisjunction, which occurs most often during the formation of reproductive cells, the egg and sperm. Normal cell division, or meiosis, ensures that each gamete receives only one copy of each chromosome pair. Nondisjunction represents a failure of these chromosome copies to separate properly during one of the two meiotic divisions.
If the separation error occurs during meiosis I, the homologous chromosome pairs fail to disjoin, resulting in two gametes that carry both copies of the chromosome and two that carry none. If the error happens during meiosis II, the sister chromatids fail to separate, leading to one gamete with an extra chromosome, one missing a chromosome, and two normal gametes. When a gamete containing this extra chromosome fertilizes a normal gamete, the resulting embryo has three copies of that chromosome, a trisomy.
While nondisjunction accounts for the vast majority of trisomy cases, a smaller proportion results from a structural change known as an unbalanced translocation. A translocation occurs when a piece of one chromosome breaks off and attaches to another, non-homologous chromosome.
An unbalanced translocation results when an individual inherits the rearranged chromosome and also receives the normal copy from the other parent. This leads to a duplication of the genes on the translocated segment, creating a functional trisomy of a chromosomal region. For example, a parent carrying a balanced Robertsonian translocation involving chromosome 21 may pass on an unbalanced set, resulting in Trisomy 21.
Common Types of Trisomy
The viability of a trisomy depends on the size and gene content of the affected chromosome, with the majority resulting in miscarriage. Only a few trisomies of the autosomes (non-sex chromosomes) allow for survival past birth. These are categorized by the number of the affected chromosome, the most frequently observed being Trisomy 21, or Down Syndrome.
Trisomy 21 occurs in approximately one in 700 live births and is the most common chromosomal cause of intellectual disability. Individuals typically have distinct facial features, characteristic growth patterns, and varying degrees of cognitive impairment. Congenital heart defects are also prevalent, affecting around 40% of individuals with Down Syndrome and often requiring corrective medical intervention.
The second most common viable trisomy is Trisomy 18, or Edwards Syndrome, which has a severe clinical presentation. This condition occurs in about one in 5,000 live births, though many affected pregnancies do not reach full term. Edwards Syndrome is characterized by severe intellectual and developmental delays, low birth weight, and multiple congenital anomalies.
Physical characteristics often include a small head and jaw, low-set ears, and an overlapping of the fingers with clenched fists. Life expectancy is limited due to the severity of internal organ malformations, particularly heart and kidney defects. Most infants with this condition do not survive past their first year.
The most severe of the common trisomies is Trisomy 13, or Patau Syndrome, occurring in approximately one in 16,000 live births. Patau Syndrome is defined by profound intellectual disability and extensive structural defects affecting the central nervous system, heart, and face. A hallmark is the failure of the forebrain to divide properly, known as holoprosencephaly.
Other frequent anomalies include cleft lip and palate, extra fingers or toes (polydactyly), and microphthalmia (small or poorly developed eyes). Due to the multiplicity of life-threatening malformations, the median survival rate is very short, often measured in days or weeks.
The Cellular Consequences of Extra DNA
The widespread disruption caused by an extra chromosome is due to gene dosage imbalance. Chromosomes carry hundreds to thousands of genes, and having three copies means all genes on that chromosome are overexpressed. The cellular machinery transcribes these genes at roughly 1.5 times the normal level, leading to an overabundance of corresponding proteins.
This excess protein production is the primary source of cellular stress in trisomic cells. The cell’s networks operate with precise stoichiometry, meaning components must be present in specific, balanced quantities. An increase in one set of proteins, even by 50%, throws off this equilibrium, affecting the entire cellular environment.
The molecular consequences extend beyond the genes on the trisomic chromosome itself. The extra chromosome causes a cascade of downstream effects, disrupting the expression of genes located on other, non-trisomic chromosomes. This systemic disruption of the whole genome’s balance drives the complex pathology seen in trisomy syndromes.
One major consequence is the overwhelming of the cell’s proteostasis network, which maintains protein quality control. This network includes chaperones (which help proteins fold correctly) and the proteasome (which degrades misfolded or excess proteins). In trisomic cells, constant overproduction can exceed this capacity, leading to the accumulation of misfolded proteins and cellular aggregates, resulting in proteotoxic stress.
This molecular chaos also impacts fundamental cellular processes, including metabolism and the cell cycle. Trisomic cells often exhibit altered metabolic demands, such as an increased need for certain amino acids like serine, which is linked to lipid synthesis and cell proliferation. The structural integrity of the cell can also be compromised, sometimes resulting in abnormal nuclear morphology. This dysfunction reflects the disruption of tightly regulated developmental signaling pathways during embryogenesis.