A chromosome is a package of DNA. Humans normally have 23 pairs of chromosomes, with one copy inherited from each parent. Chromosome 21 is the smallest of the 22 non-sex chromosomes (autosomes), making up approximately 1.5 to 2% of the total genetic material. Despite its small size, it holds an estimated 200 to 300 genes that coordinate a wide range of developmental processes.
The Primary Condition: Trisomy 21
The most common consequence of having an extra Chromosome 21 is Trisomy 21, which accounts for over 90% of cases. This means every cell contains three copies of the chromosome instead of the usual two. The extra genetic material disrupts the normal balance of gene expression, leading to associated physical and intellectual features.
The extra chromosome typically originates from a mistake during cell division called non-disjunction, where a pair of chromosomes fails to separate correctly during egg or sperm formation. In nearly all cases, this error occurs in the maternal egg cell. The incidence of non-disjunction increases with the mother’s age, although most affected babies are born to women under 35 years old.
Individuals with Trisomy 21 experience developmental delays and mild to moderate intellectual disability. Physical characteristics include low muscle tone, a flattened facial profile, and a single deep crease across the palm. Medical complications are frequent; approximately 40 to 50% of affected infants are born with congenital heart defects that often require surgery.
Diagnosis can occur prenatally through screening tests followed by diagnostic procedures like a karyotype. Postnatal management involves a multidisciplinary approach focused on early intervention, including physical, occupational, and speech therapies, which improve outcomes. Regular health screenings are implemented to manage associated conditions, such as hearing loss, vision problems, and thyroid issues.
While Trisomy 21 is the most common form, the extra chromosome can manifest in other ways. Translocation Trisomy 21 occurs when an extra full or partial copy of Chromosome 21 attaches to another chromosome, usually Chromosome 14. A rarer form is mosaicism, where the extra chromosome is present in only some of the body’s cells, often resulting in a milder presentation.
Large Scale Structural Variations
Rearrangements involving only a portion of Chromosome 21 can lead to various genetic syndromes. These structural variations include the loss of a section (a deletion) or the presence of an extra copy of a specific segment (a partial duplication). The severity of the resulting condition depends on the size and location of the segment involved.
A partial deletion of the long arm, termed 21q deletion syndrome, results in symptoms that differ from Trisomy 21. These symptoms sometimes include severe intellectual disability, specific facial features, and developmental delays. Conversely, a partial duplication of the long arm (partial trisomy 21) results in an extra set of genes for only that segment, often producing a clinical picture similar to Trisomy 21 but with varying severity.
Translocations can be categorized as either balanced or unbalanced. An unbalanced translocation results in an extra dose of genetic material and causes a syndrome. A balanced translocation involves an exchange of material between Chromosome 21 and another chromosome without any net gain or loss of genes, meaning the individual is typically healthy.
A healthy parent carrying a balanced translocation involving Chromosome 21 has an increased risk of passing an unbalanced version to their offspring, leading to conditions like translocation Trisomy 21. Another rare structural anomaly is the ring chromosome 21, which forms when the ends break off and fuse together in a circle. This results in a highly heterogeneous condition, often leading to the loss of genetic material from the tips of the chromosome arms.
Essential Genes and Their Role in Other Diseases
The effects of having an extra Chromosome 21 are driven by the overexpression of its genes, leading to a 50% increase in the amount of protein produced by each gene. One of the most studied genes is the Amyloid Precursor Protein ($APP$) gene. This gene provides instructions for making the $APP$ protein, which, when broken down, creates the Amyloid-Beta ($A\beta$) peptide.
The $A\beta$ peptide forms the amyloid plaques that accumulate in the brains of people with Alzheimer’s disease. Because individuals with Trisomy 21 have three copies of the $APP$ gene, they produce an excessive amount of $A\beta$ peptide. Consequently, nearly all individuals with a full extra Chromosome 21 develop the brain neuropathology of Alzheimer’s disease by age 40.
Other Chromosome 21 genes increase the risk for certain blood cancers. Genes like $DSCR1$ and $DYRK1A$ are overexpressed, and both function to inhibit the calcineurin signaling pathway. This gene overexpression cooperates with other acquired mutations to increase the risk of childhood leukemia, particularly acute megakaryoblastic leukemia.
Conversely, this same gene dosage imbalance confers a protective effect against most forms of solid tumors. Research suggests that the overexpression of $DSCR1$ and $DYRK1A$ may suppress the growth of blood vessels that tumors need to grow. This indicates that having an extra Chromosome 21 causes a complex suite of effects, increasing the risk for some diseases while reducing the risk for others.