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Chromosome 21
The smallest human autosome - trisomy 21 causes Down syndrome, the most common survivable chromosomal disorder.
Schematic of chromosome 21 showing the short (p) and long (q) arms. Arm ratio per GRCh38 - banding schematic.
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Overview
Chromosome 21 is the smallest of the 22 autosomes, representing roughly 1.5 per cent of the total human genome. Despite its compact size of 46.7 million base pairs, it carries approximately 234 protein-coding genes whose dosage imbalance can profoundly affect development and health. The chromosome is acrocentric, meaning its centromere sits near one end, creating a very short p arm and a much longer q arm where nearly all genes reside.
Clinically, chromosome 21 is synonymous with Down syndrome, the condition that arises when a person inherits three copies instead of the usual two. Trisomy 21 is the leading chromosomal cause of intellectual disability worldwide. The chromosome also harbours genes implicated in Alzheimer disease, leukaemia predisposition, and progressive myoclonus epilepsy, underscoring its relevance across lifespan and medical speciality.
Because trisomy 21 can be detected through non-invasive prenatal testing and ultrasound screening, chromosome 21 sits at the heart of the NHS Fetal Anomaly Screening Programme. Understanding its structure and gene content helps families and healthcare professionals navigate prenatal counselling, postnatal support, and long-term care planning.
Structure
Like all acrocentric chromosomes (13, 14, 15, 21, and 22), chromosome 21 has its centromere positioned very close to one tip, yielding a short p arm and a long q arm. The short arm carries clusters of ribosomal RNA genes that help build the cell's protein-manufacturing machinery; these sequences form part of the nucleolar organiser region visible during cell division. The majority of protein-coding genes sit on the q arm, which extends from the centromere to the telomere at the far end.
At the molecular level, chromosome 21's DNA double helix is wrapped around histone proteins to form repeating units called nucleosomes, which then coil into chromatin fibres. During cell division, this chromatin condenses dramatically, transforming into the compact X-shaped structure familiar from karyotype images. This packaging must be carefully regulated: genes that need to be active remain relatively open and accessible, while those that should be silent are packed more tightly and chemically modified to stay switched off.
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Notable regions
The band designated 21q22.13 encompasses what researchers have called the Down syndrome critical region. Early mapping studies suggested that triplication of genes within this interval was sufficient to produce many of the characteristic features of Down syndrome, including intellectual disability and distinctive facial appearance. Subsequent work has shown the picture is more nuanced, with contributions from genes across the entire long arm, but 21q22.13 remains a focal point for understanding genotype-phenotype relationships in trisomy 21.
Just upstream, at 21q21.3, sits APP, the gene encoding amyloid precursor protein. Having three copies of APP, as occurs in Down syndrome, is thought to contribute to increased Alzheimer disease risk in individuals with trisomy 21. Duplication of APP alone, even without full trisomy, can cause early-onset familial Alzheimer disease, demonstrating that gene dosage matters profoundly for this locus.
Further along the long arm at 21q22.3 lies RUNX1, a transcription factor gene critical for blood-cell development. Pathogenic variants in RUNX1 cause familial platelet disorder with propensity to acute myeloid leukaemia, a condition in which affected family members have low platelet counts and face elevated leukaemia risk. The short p arm, though gene-poor, contributes ribosomal RNA sequences essential for assembling ribosomes in the nucleolus, a function shared with the other acrocentric chromosomes.
Notable genes
Beyond APP and RUNX1, chromosome 21 carries several genes with distinct clinical or biological roles. One gene we do cover in detail is CSTB at 21q22.3, which encodes cystatin B, a protein that regulates enzymes called cathepsins. Loss-of-function variants or an unstable repeat expansion in CSTB cause Unverricht-Lundborg disease, a form of progressive myoclonus epilepsy characterised by seizures, myoclonic jerks, and ataxia, typically presenting in late childhood or adolescence. The same chromosomal region also houses KCNE1, mutations in which can cause Jervell and Lange-Nielsen syndrome, a recessive disorder combining profound hearing loss with life-threatening cardiac arrhythmias. These single-gene conditions illustrate how disruption of individual loci on chromosome 21 can produce distinct clinical phenotypes quite separate from the effects of whole-chromosome trisomy.
Chromosomal disorders
Trisomy 21, commonly known as Down syndrome, arises when an individual has three copies of chromosome 21 instead of two. This typically results from nondisjunction during meiosis, an error in which chromosome pairs fail to separate properly, leaving one egg or sperm with an extra copy. Most cases involve free trisomy, meaning the entire chromosome is present in triplicate in every cell. A smaller proportion result from unbalanced Robertsonian translocations, in which the long arm of chromosome 21 fuses to another acrocentric chromosome, or from mosaic trisomy 21, where only some cells carry the extra copy.
The clinical features of Down syndrome are variable but often include characteristic facial features, intellectual disability of varying degree, congenital heart defects, increased susceptibility to infections and autoimmune conditions, and higher lifetime risk of leukaemia and early-onset dementia. Life expectancy has improved markedly over recent decades with advances in cardiac surgery, infection management, and supportive care, and many people with Down syndrome now live into their sixties, compared with life expectancy in the twenties just five decades ago.
Partial trisomy or monosomy of chromosome 21 is rare and typically arises from unbalanced chromosomal rearrangements inherited from a parent who carries a balanced translocation. The clinical picture depends on which segments are duplicated or missing and can range from mild developmental delay to severe malformations. Such cases are usually detected on karyotype or chromosomal microarray analysis and prompt referral to clinical genetics for family studies and tailored counselling.
Prenatal screening & diagnosis
Chromosome 21 abnormalities, particularly trisomy 21, are among the primary targets of the NHS Fetal Anomaly Screening Programme. The combined first-trimester screening uses maternal age, ultrasound measurement of nuchal translucency (fluid at the back of the baby's neck), and biochemical markers in maternal blood to estimate the chance that the pregnancy is affected by Down syndrome, Edwards syndrome (trisomy 18), or Patau syndrome (trisomy 13).
Non-invasive prenatal testing, or NIPT, analyses cell-free foetal DNA circulating in maternal blood and can detect trisomy 21 with high sensitivity and specificity during the first trimester. NIPT has been available through the NHS since 2021 for women with higher-chance combined screening results, and some families choose to access it privately. It is important to understand that NIPT is a screening test, not a diagnostic one: a high-chance NIPT result is followed by offer of diagnostic testing via chorionic villus sampling or amniocentesis, both of which provide foetal cells for karyotyping or chromosomal microarray to confirm or exclude trisomy 21.
Ultrasound may reveal soft markers suggestive of Down syndrome, such as heart defects, duodenal atresia, or shorter-than-expected limb bones, but these findings are not specific and must be interpreted alongside screening results and family history. Families who receive a prenatal diagnosis of trisomy 21 are offered counselling with a foetal-medicine specialist and a clinical geneticist or genetic counsellor, information about the condition, and time to consider their options, which may include continuing the pregnancy with planning for postnatal support or pursuing termination in accordance with UK law.
Inheritance & recurrence
The vast majority of Down syndrome cases result from de novo nondisjunction, meaning the trisomy occurred as a spontaneous error during formation of the egg or sperm and was not inherited from either parent. In these free-trisomy cases, the recurrence risk in a subsequent pregnancy is low but slightly elevated compared with the background population risk. Maternal age is the strongest known risk factor, with the chance of trisomy 21 increasing substantially in pregnancies conceived after age 35.
When Down syndrome arises from an unbalanced Robertsonian translocation, one parent may carry a balanced version of the same translocation, in which case the recurrence risk can be considerably higher depending on which chromosomes are involved and which parent carries the rearrangement. Parental karyotyping is therefore recommended whenever translocation Down syndrome is diagnosed, so that accurate recurrence-risk figures and reproductive options, including preimplantation genetic testing, can be discussed. Referral to a clinical genetics service is standard practice in these families to ensure that siblings and extended relatives who might carry the translocation are identified and offered appropriate counselling and testing.
Frequently asked questions
What causes most cases of Down syndrome?
Most cases of Down syndrome result from a random error called nondisjunction, in which chromosome 21 fails to separate properly during the formation of an egg or sperm. This leaves the embryo with three copies of chromosome 21 instead of two. Maternal age is the strongest known risk factor, but Down syndrome can occur in pregnancies at any age.
Can Down syndrome be detected before birth?
Yes. The NHS offers combined first-trimester screening, which estimates the chance of Down syndrome using ultrasound and blood tests. Non-invasive prenatal testing, available for higher-chance pregnancies, analyses foetal DNA in maternal blood. A definitive diagnosis requires chorionic villus sampling or amniocentesis to examine foetal chromosomes directly.
If my child has Down syndrome, will my next pregnancy be affected?
In most cases, the recurrence risk is low but slightly higher than the background population risk, influenced primarily by maternal age. If your child's Down syndrome resulted from a translocation, one parent may carry a balanced rearrangement, which can raise recurrence risk. Your clinical genetics team will arrange parental karyotyping and provide personalised counselling.
Are there other conditions linked to chromosome 21 besides Down syndrome?
Yes. Pathogenic variants in individual genes on chromosome 21 cause distinct conditions without affecting chromosome number. For example, variants in CSTB cause Unverricht-Lundborg disease, a form of progressive epilepsy, while variants in RUNX1 lead to familial platelet disorder with leukaemia predisposition. Duplication of the APP gene alone can cause early-onset Alzheimer disease.
Why is chromosome 21 called acrocentric?
Acrocentric means the centromere sits very close to one end, creating a short p arm and a long q arm. The short arm of chromosome 21 carries clusters of ribosomal RNA genes that help cells build ribosomes. This structure is shared with chromosomes 13, 14, 15, and 22, and influences how these chromosomes can rearrange in translocations.
Launch-set genes on chromosome 21
Genes on this chromosome that currently have dedicated pages in the library. This list grows as we publish more.