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Chromosome 22
The first human chromosome fully sequenced - home of the 22q11.2 DiGeorge-syndrome region and the BCR partner of BCR-ABL.
Schematic of chromosome 22 showing the short (p) and long (q) arms. Arm ratio per GRCh38 - banding schematic.
Available at Jeen Health
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Overview
Chromosome 22 spans approximately 50.8 million base pairs and encodes around 488 protein-coding genes, representing roughly 1.5% of the human genome. Despite its modest size, it holds exceptional clinical and historical importance: in 1999, an international consortium published the first complete sequence of a human chromosome, choosing chromosome 22 for its compact size and rich gene content. The chromosome is acrocentric, meaning the centromere sits very close to one end, creating a short arm (p) that carries repetitive ribosomal-RNA genes and a long arm (q) that houses the bulk of protein-coding sequences. The long arm includes regions associated with some of the most widely studied genetic conditions, including the 22q11.2 deletion syndrome and neurofibromatosis type 2.
Clinically, chromosome 22 is best known for microdeletion syndromes and chromosomal translocations. The 22q11.2 deletion, affecting 1 in 2,000 to 1 in 4,000 live births, is the most common microdeletion syndrome and presents with a broad spectrum of developmental and immunological features. Additionally, the BCR gene at 22q11.23 is a frequent partner in the reciprocal translocation t(9;22), which generates the BCR-ABL1 fusion oncogene seen in chronic myeloid leukaemia and some forms of acute lymphoblastic leukaemia. These clinical associations have made chromosome 22 a focal point for molecular cytogenetics, prenatal screening, and targeted therapies within the NHS Genomic Medicine Service.
Structure
Like all acrocentric chromosomes (13, 14, 15, 21, and 22), chromosome 22 has a centromere positioned near one end, dividing it into a very short p arm and a longer q arm. The short arm consists almost entirely of tandem repeats encoding ribosomal RNA, which cluster together during cell division to form nucleoli, the cellular factories for ribosome assembly. Because these sequences are highly repetitive and not unique to chromosome 22, they were initially omitted from the published sequence but have since been characterised through long-read sequencing technologies. The long arm contains the vast majority of the chromosome's genes and regulatory elements, organised into distinct cytogenetic bands visible under a microscope when stained during metaphase.
At the molecular level, the DNA double helix of chromosome 22 wraps around histone proteins to form nucleosomes, which compact further into chromatin fibres. During cell division, chromatin condenses into the familiar X-shaped chromosome visible under the microscope. This hierarchical packaging allows roughly 50 million base pairs to fit inside the nucleus of every cell, while still permitting controlled access for transcription, replication, and DNA repair. The acrocentric architecture also makes chromosome 22 susceptible to non-allelic homologous recombination between repetitive sequences on the long arm, a mechanism that underlies many of the recurrent microdeletions and duplications observed in clinical genetics.
Video: What is a karyotype?
Notable regions
The 22q11.2 band is the most clinically significant region on chromosome 22. It contains a cluster of low-copy repeats (segmental duplications) that flank a roughly three-million-base-pair interval. Recombination between these repeats during meiosis can delete the intervening segment, removing approximately 90 genes and giving rise to 22q11.2 deletion syndrome. This condition, historically known as DiGeorge syndrome or velocardiofacial syndrome depending on the clinical presentation, is characterised by heart defects, immune dysfunction due to thymus underdevelopment, palatal abnormalities, and learning difficulties. The TBX1 gene within the deleted region is considered a major contributor to the cardiac and craniofacial features, though the full phenotype results from loss of multiple dosage-sensitive genes.
Further along the long arm, at 22q11.23, sits the BCR gene (breakpoint cluster region). This gene became famous when researchers discovered that a reciprocal translocation between chromosomes 9 and 22 fuses part of BCR with the ABL1 tyrosine kinase gene from chromosome 9. The resulting BCR-ABL1 fusion protein drives uncontrolled white-blood-cell proliferation in chronic myeloid leukaemia and some cases of acute lymphoblastic leukaemia. The translocation creates an abnormally short chromosome 22, historically termed the Philadelphia chromosome after the city where it was first described in 1960. Targeted therapies, such as tyrosine-kinase inhibitors, have transformed outcomes for patients with BCR-ABL1-positive leukaemias, and detection of the translocation is part of standard haematological diagnostics within the NHS.
The 22q12.2 band harbours the NF2 gene, which encodes merlin, a tumour-suppressor protein that regulates cell-shape and contact-dependent growth inhibition. Pathogenic variants in NF2 cause neurofibromatosis type 2, a condition characterised by bilateral vestibular schwannomas (nerve-sheath tumours affecting hearing and balance), meningiomas, and spinal tumours. Unlike neurofibromatosis type 1 (caused by a gene on chromosome 17), NF2 typically presents in early adulthood with progressive hearing loss or tinnitus. Clinical management involves regular MRI surveillance and multidisciplinary input, often coordinated through specialist centres linked to the NHS Genomic Medicine Service.
Notable genes
Beyond the genes already mentioned, chromosome 22 carries CHEK2 at 22q12.1, encoding a checkpoint kinase involved in DNA-damage response. Pathogenic variants in CHEK2 moderately increase the risk of breast, colorectal, and prostate cancers, and cascade testing of relatives is sometimes offered through NHS clinical genetics when a CHEK2 variant is identified in a cancer patient. SMARCB1, also on the long arm, encodes a core subunit of chromatin-remodelling complexes; germline loss-of-function variants cause rhabdoid-tumour predisposition syndrome, one of the most aggressive paediatric cancers, while mosaic or somatic variants contribute to Coffin-Siris syndrome, a developmental disorder with intellectual disability and characteristic facial features.
USP18, located within the 22q11.21 region often deleted in DiGeorge syndrome, regulates type-I interferon signalling. Biallelic pathogenic variants in USP18 lead to a severe autoinflammatory condition sometimes termed pseudo-TORCH syndrome, reflecting its clinical overlap with congenital infections. The NEFH gene at 22q12.2 encodes the heavy-chain subunit of neurofilaments, structural proteins that maintain the calibre and conductivity of nerve axons; variants in NEFH have been associated with Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis in research cohorts, though the gene is not routinely included in many diagnostic gene panels.
Chromosomal disorders
The 22q11.2 deletion syndrome is the archetypal disorder of chromosome 22 and one of the most common genomic conditions recognised at birth. Most cases arise de novo through non-allelic homologous recombination between low-copy repeats during parental meiosis, though roughly 10% are inherited from a mildly affected or undiagnosed parent. The clinical spectrum is extremely variable: some individuals present in infancy with cyanotic heart disease and severe T-cell immunodeficiency, while others are diagnosed in childhood with speech delay and learning difficulties, or even in adulthood during family cascade testing. Key features include conotruncal heart defects (tetralogy of Fallot, interrupted aortic arch), hypocalcaemia due to parathyroid hypoplasia, recurrent infections from thymic hypoplasia, velopharyngeal insufficiency, and increased risk of psychiatric conditions such as schizophrenia and anxiety disorders in adolescence and adulthood.
Diagnosis is typically confirmed by chromosomal microarray or fluorescence in-situ hybridisation (FISH) targeting the 22q11.2 region, and affected individuals are usually managed by multidisciplinary teams including cardiology, immunology, endocrinology, and clinical genetics. Recurrence risk is 50% for each pregnancy when one parent carries the deletion, following autosomal-dominant inheritance, whereas the recurrence risk after one affected child born to parents without the deletion is low but not negligible due to the possibility of germline mosaicism. A reciprocal 22q11.2 duplication also exists and may present with developmental delay, growth abnormalities, and a smaller range of congenital anomalies, though its clinical impact is generally milder and more variable.
Chromosome 22 is not typically involved in whole-chromosome aneuploidy compatible with live birth; complete trisomy 22 and monosomy 22 are almost always lethal in utero. Mosaic trisomy 22, where only some cells carry three copies, has been reported in rare cases and presents with severe developmental delay, growth restriction, and multiple congenital anomalies. However, most prenatally detected trisomy 22 findings reflect confined placental mosaicism, where the abnormality is limited to placental tissue and does not affect the fetus, underscoring the importance of confirmatory testing through amniocentesis or detailed ultrasound.
Prenatal screening & diagnosis
Abnormalities of chromosome 22 are not part of the core panel screened by non-invasive prenatal testing (NIPT) for common trisomies (13, 18, 21), because whole-chromosome aneuploidies of 22 are rarely viable. However, some extended NIPT platforms marketed privately or used in research settings can flag large deletions or duplications, including 22q11.2 microdeletions, through analysis of cell-free foetal DNA in maternal blood. At present, most 22q11.2 deletions are identified either postnatally following clinical suspicion or prenatally when a structural anomaly (such as a heart defect or thymic hypoplasia) is detected on routine ultrasound, prompting invasive testing with chromosomal microarray.
When a fetus is found to have a congenital heart defect during the 18- to 20-week anomaly scan offered through the NHS Fetal Anomaly Screening Programme, chromosomal microarray or FISH for 22q11.2 is often offered alongside karyotyping to look for the deletion. If confirmed, parents receive detailed counselling about the range of outcomes, the availability of specialist paediatric care, and the option of further testing to clarify whether either parent carries the deletion. Because phenotypic expression is so variable, predicting the severity for an individual fetus remains challenging, and families are supported by clinical genetics teams and, where available, foetal-medicine specialists.
Inheritance & recurrence
Most 22q11.2 deletions occur de novo, meaning neither parent carries the deletion and the event arose sporadically during the formation of egg or sperm. In roughly 10% of cases, however, one parent is found to carry the deletion, sometimes with mild or previously unrecognised features, and the condition then follows autosomal-dominant inheritance with a 50% recurrence risk in each pregnancy. For couples who have had one child with a de-novo deletion, the recurrence risk is generally quoted at around 1%, slightly above the population baseline, to account for the theoretical possibility of low-level germline mosaicism. Parental testing by microarray or FISH is therefore recommended following any new diagnosis of 22q11.2 deletion syndrome to clarify recurrence risk and inform wider family screening.
Pathogenic variants in single genes on chromosome 22, such as NF2 or CHEK2, follow classical mendelian inheritance. NF2-related schwannomatosis is autosomal dominant with high penetrance, meaning children of an affected parent have a 50% chance of inheriting the variant, though the age of onset and tumour burden can vary. CHEK2 variants also follow autosomal-dominant inheritance but confer moderate rather than high cancer risk, and many carriers never develop cancer, reflecting incomplete penetrance and the influence of additional genetic and environmental factors. Families identified with pathogenic variants in these genes are typically offered genetic counselling and, where appropriate, cascade testing of at-risk relatives through the NHS Genomic Medicine Service.
Frequently asked questions
What is 22q11.2 deletion syndrome, and how common is it?
22q11.2 deletion syndrome, also known as DiGeorge syndrome or velocardiofacial syndrome, occurs when a small piece of the long arm of chromosome 22 is missing. It affects 1 in 2,000 to 1 in 4,000 babies and is the most common microdeletion syndrome. Features can include heart defects, immune problems, cleft palate, learning difficulties, and an increased risk of mental-health conditions later in life, though severity varies widely between individuals.
Can 22q11.2 deletion syndrome be detected before birth?
Yes, if a structural abnormality such as a heart defect is seen on ultrasound during pregnancy, chromosomal microarray or FISH testing on a sample obtained by amniocentesis can confirm whether the 22q11.2 deletion is present. Some extended non-invasive prenatal tests can also screen for large deletions, though these are not yet part of standard NHS antenatal care. If the deletion is found, parents are offered genetic counselling to discuss what it might mean for their baby.
What is the Philadelphia chromosome, and how is it related to chromosome 22?
The Philadelphia chromosome is an abnormally short chromosome 22 that results from a swap of genetic material between chromosomes 9 and 22. This translocation fuses part of the BCR gene on chromosome 22 with the ABL1 gene on chromosome 9, creating a hybrid gene that drives chronic myeloid leukaemia and some types of acute lymphoblastic leukaemia. Targeted medicines called tyrosine-kinase inhibitors can block the abnormal protein and are a mainstay of treatment within the NHS.
If my child has been diagnosed with a 22q11.2 deletion, should I be tested too?
Yes, it is generally recommended that both parents have a blood test to check whether either of them carries the same deletion. In about 90% of cases, neither parent has it and the deletion occurred spontaneously, but in roughly 10% of cases one parent carries the deletion, sometimes with mild features. Knowing whether a parent has the deletion helps estimate the chance of it happening again in future pregnancies and may prompt assessment of other family members.
Are there other conditions linked to chromosome 22 besides DiGeorge syndrome?
Yes, chromosome 22 is home to several important genes. Pathogenic variants in the NF2 gene cause neurofibromatosis type 2, which leads to nerve-sheath tumours affecting hearing and balance. Changes in CHEK2 moderately increase the risk of breast and other cancers. The SMARCB1 gene, when altered, can cause rhabdoid tumours in children or contribute to Coffin-Siris syndrome. Each of these conditions has its own inheritance pattern and clinical management pathway, usually coordinated through NHS clinical genetics services.
Launch-set genes on chromosome 22
Genes on this chromosome that currently have dedicated pages in the library. This list grows as we publish more.