Monosomy 22, the complete or partial loss of one copy of chromosome 22, spans a surprisingly wide range of conditions depending on how much of the chromosome is missing and whether every cell in the body is affected. A full loss of chromosome 22 in all cells is almost universally fatal before birth, but partial deletions of specific regions on this chromosome cause two of the most studied genetic syndromes in medicine. And in certain tumors, the loss of chromosome 22 within cancer cells turns out to be one of the most common chromosomal changes driving tumor growth.
Why Complete Monosomy 22 Is Nearly Always Lethal
Chromosome 22 is one of the smallest human chromosomes, but it still carries hundreds of genes essential for normal development. When an embryo ends up with only one copy instead of two, the resulting shortage of gene products is so severe that development typically fails in the first weeks of pregnancy. Most embryos with full monosomy 22 are lost as very early miscarriages, often before a pregnancy is even recognized.
Studies analyzing tissue from first-trimester miscarriages find that chromosomal abnormalities are the leading cause of early pregnancy loss. In one analysis of 165 cases with chromosomal abnormalities among miscarriage specimens, autosomal monosomy was rare compared to trisomy, and the monosomies detected involved only chromosomes 21 and X rather than chromosome 22.1Cytogenetic and Genome Research. Cytogenetic Analysis of the Products of Conception After Spontaneous Abortion in the First Trimester Chromosome 22 did appear in that study, but in the context of complex abnormalities rather than straightforward monosomy. The near-total absence of full monosomy 22 among even miscarried pregnancies suggests that embryos with this condition fail so early that they are rarely captured in clinical sampling.
The reason autosomal monosomies are far more lethal than trisomies comes down to gene dosage. Having an extra copy of a chromosome means cells produce roughly 50 percent more of those gene products, which is disruptive but sometimes survivable. Having only one copy means cells produce roughly half the needed amount of each protein encoded on that chromosome. For chromosome 22, that halving is incompatible with the earliest stages of embryonic life.
Mosaic Monosomy 22
The one scenario in which a person can survive with monosomy 22 is mosaicism, where only a fraction of cells in the body have lost one copy of chromosome 22 while the remaining cells retain the normal two copies. This happens when a chromosome is lost during cell division after fertilization rather than being absent from the very start.
Two main cellular errors create mosaicism. In one, called anaphase lagging, a chromosome fails to get pulled into either daughter cell during division and is simply lost, leaving one normal cell and one monosomic cell. In the other, called mitotic nondisjunction, the two copies of a chromosome both end up in the same daughter cell, producing one trisomic cell and one monosomic cell.2PubMed Central. The birth of a baby with mosaicism resulting from a known mosaic embryo transfer: a case report When either of these errors affects chromosome 22 during early embryonic development, the result is a person whose tissues contain a patchwork of normal and monosomic cells.
How severely a person is affected depends on what percentage of cells lost the chromosome and which tissues those cells ended up in. A case report of a girl with a ring chromosome 22, a structurally altered version of the chromosome prone to being lost during cell division, illustrates this variability. Testing of her blood found that about 8 percent of her white blood cells had monosomy 22, while testing of her skin fibroblasts showed about 24 percent were monosomic.3PubMed Central. Compound phenotype in a girl with r(22), concomitant microdeletion 22q13.32-q13.33 and mosaic monosomy 22 Different tissues can have very different proportions of affected cells, which makes clinical presentation highly variable from one person to the next even when they share the same underlying chromosomal problem.
22q11.2 Deletion Syndrome
By far the most common and best-studied form of partial monosomy 22 is 22q11.2 deletion syndrome, in which a small segment of the long arm of chromosome 22 is missing. This condition has historically gone by several names, including DiGeorge syndrome and velocardiofacial syndrome, depending on which features were most prominent in the patient who happened to be described first. They are now understood to be the same underlying genetic condition.
The deletion occurs in roughly 1 in every 1,000 fetuses, making it the most common chromosomal microdeletion disorder known.4Nature Reviews Disease Primers. 22q11.2 deletion syndrome The first clinical description in English appeared in the 1960s, when children were identified with a triad of immune deficiency, low calcium due to underactive parathyroid glands, and congenital heart defects. Since then, the recognized spectrum of the condition has expanded enormously to include palatal abnormalities, gastrointestinal and kidney problems, autoimmune disease, cognitive delays, and psychiatric illness.
In children, the features that tend to bring the condition to clinical attention include congenital heart defects, recurrent infections, hypernasal speech, feeding difficulties, and delays in both speech and general development.5PubMed Central. Deletion Syndrome 22q11.2: A Systematic Review The presentation changes with age. Adults may come to diagnosis through psychiatric symptoms, autoimmune conditions, or the birth of an affected child, sometimes having gone unrecognized themselves for decades.
The region that is deleted contains low copy repeats, segments of DNA that are very similar to each other and sit at different positions along chromosome 22. These repeats can misalign during egg or sperm formation, leading to an abnormal exchange of genetic material between them that deletes the stretch of DNA in between.6PubMed Central. The 22q11 low copy repeats are characterized by unprecedented size and structural variability This mechanism, called nonallelic homologous recombination, is why the deletion recurs at this particular spot on chromosome 22 far more often than random chance would predict.
Most cases arise as new events rather than being inherited from a parent. However, a person who carries the deletion has a 50 percent chance of passing it on to each child.7PubMed. Genetic counseling for the 22q11.2 deletion Rare instances of mosaicism in a parent’s eggs or sperm can also give unaffected parents a small but real chance of having more than one affected child.
Phelan-McDermid Syndrome
At the opposite end of chromosome 22’s long arm sits a different deletion region responsible for Phelan-McDermid syndrome, formally known as 22q13.3 deletion syndrome. This condition shares some superficial overlap with 22q11.2 deletion syndrome in that both involve missing material from chromosome 22, but the genes lost, the clinical features, and the underlying biology are quite different.
The hallmark features of Phelan-McDermid syndrome are global developmental delay, moderate to severe intellectual disability, absent or severely delayed speech, and low muscle tone from birth. Over half of affected individuals also show autism or autism-like behaviors, making this one of the recognized genetic causes of autism spectrum disorder.8PubMed Central. The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome) Growth is typically normal, and the facial differences associated with the syndrome tend to be subtle.
Nearly all of these deletions include a gene called SHANK3, which produces a protein critical for the structure and function of connections between nerve cells. Animal studies and cell experiments have confirmed that losing one working copy of SHANK3 disrupts how nerve cells communicate, which is thought to account for most of the neurological features. But the size of the deletion matters too. Larger deletions that extend further along the chromosome are associated with more features, including abnormalities of the toenails, large hands, tall stature, and differences in head shape, suggesting that additional genes beyond SHANK3 contribute to the full clinical picture.9Journal of Medical Genetics. Association between deletion size and important phenotypes expands the genomic region of interest in Phelan–McDermid syndrome (22q13 deletion syndrome)
The deletion at 22q13.3 can arise in several ways. It may be a straightforward deletion, a consequence of ring chromosome 22 instability, or the result of a balanced chromosomal rearrangement carried by one parent. Each mechanism carries a different risk of recurrence in future pregnancies.10European Journal of Medical Genetics. Consensus recommendations on counselling in Phelan-McDermid syndrome, with special attention to recurrence risk and to ring chromosome 22
Monosomy 22 in Tumors
Outside of inherited or congenital conditions, monosomy 22 plays a prominent role in several types of cancer. Here the chromosome loss happens within tumor cells only, not in the person’s normal tissues. It is an acquired, somatic event that contributes to tumor growth by removing a working copy of a tumor suppressor gene.
Meningiomas, the most common primary brain tumors in adults, are the best-known example. Loss of one copy of chromosome 22 is the single most frequent chromosomal alteration found in these tumors, and it is often paired with mutations in the NF2 gene, a tumor suppressor that sits on chromosome 22.11PubMed Central. Genetic/molecular alterations of meningiomas and the signaling pathways targeted The classic two-hit model of cancer applies here: one copy of the NF2 gene is knocked out by the chromosomal loss, and the remaining copy is inactivated by a point mutation or other localized damage. Studies of sporadic meningiomas have found that all NF2-mutated cases in some cohorts also showed monosomy 22, reinforcing the link between the two events.12PubMed Central. Association between mutation of the NF2 gene and monosomy 22 in menopausal women with sporadic meningiomas
Schwannomas, benign tumors that arise from the insulating cells wrapped around nerves, show a similar pattern. Research has found partial or complete monosomy 22 in roughly a fifth of acoustic schwannomas (the type that grows on the hearing nerve) and over half of schwannomas at other locations.13PubMed. Molecular characterization of chromosome 22 deletions in schwannomas Loss of chromosome 22 markers has also been demonstrated in spinal schwannomas, supporting the idea that a tumor suppressor gene on chromosome 22, likely NF2, is involved in schwannoma development regardless of where in the nervous system the tumor arises.14PubMed. Loss of chromosome 22 alleles in human sporadic spinal schwannomas
A different tumor suppressor on chromosome 22, SMARCB1, is the critical gene in rhabdoid tumors, a group of rare and aggressive cancers that primarily affect young children. Mutations in SMARCB1 underlie the entire spectrum of rhabdoid tumors regardless of where in the body they occur.15PubMed. Malignant Rhabdoid Tumor and Related Pediatric Tumors: Multimodality Imaging Review with Pathologic Correlation In patients who happen to have a ring chromosome 22, the inherent instability of the ring structure can cause cells to lose the chromosome entirely, providing the first “hit” against SMARCB1 and setting the stage for tumor formation if a second hit occurs in the remaining copy.16PubMed Central. Description of a new oncogenic mechanism for atypical teratoid rhabdoid tumors in patients with ring chromosome 22
How Monosomy 22 and Related Deletions Are Detected
Detecting the different forms of monosomy 22 requires different tools depending on the size of the missing segment and the clinical context. A full monosomy of chromosome 22, if it occurs in enough cells to be captured, can be seen on a standard chromosome analysis. However, the microdeletions responsible for 22q11.2 deletion syndrome and Phelan-McDermid syndrome are too small to be visible under a microscope using conventional banding techniques. These require higher-resolution methods.
Chromosomal microarray analysis, which can detect gains and losses of DNA across the entire genome at high resolution, is now the standard confirmatory test for both 22q11.2 and 22q13.3 deletions. For 22q11.2 deletion syndrome specifically, prenatal screening is possible through noninvasive prenatal screening using cell-free fetal DNA in the mother’s blood, available from about 10 weeks of pregnancy. This screening picks up roughly 70 to 83 percent of associated deletions, though its positive predictive value (meaning the chance that a positive screen reflects a true deletion) is around 40 to 50 percent, so a positive screen still requires confirmation by testing fetal cells directly through amniocentesis or chorionic villus sampling.17PubMed Central. Prenatal Screening and Diagnostic Considerations for 22q11.2 Microdeletions
For tumor-associated monosomy 22, detection is typically part of the pathologic workup after a tumor is biopsied or surgically removed. Cytogenetic testing of the tumor tissue can reveal whether chromosome 22 has been lost, and molecular techniques can pinpoint whether specific genes like NF2 or SMARCB1 have been inactivated.
Uniparental Disomy and Chromosome 22
An unusual twist related to monosomy 22 involves a phenomenon called uniparental disomy, where a person has two normal copies of chromosome 22 but both come from the same parent instead of one from each. This can happen when a trisomic embryo (one with three copies of chromosome 22) “rescues” itself by losing the extra copy, sometimes resulting in two copies from just the mother or just the father.
Research into maternal uniparental disomy for chromosome 22 has found that it does not appear to cause developmental problems on its own, apart from potential reproductive difficulties. This is an important finding because it tells geneticists that chromosome 22 does not seem to carry genes that are switched on or off depending on which parent they came from, a process called imprinting.18PubMed Central. Maternal uniparental disomy 22 has no impact on the phenotype The main concern with uniparental disomy is not imprinting but the possibility that two copies of a recessive mutation, carried silently by one parent, could both end up in the child and cause a recessive genetic disease that would otherwise have required both parents to be carriers.
Where the Errors Come From
Understanding the origins of chromosome 22 errors helps explain why they occur and, in some cases, whether age or other factors influence risk. Research into trisomy 22 (which shares mechanistic overlap with monosomy, since both arise from errors in chromosome segregation) has shown that over 96 percent of errors originate during egg formation rather than sperm formation. Among those, roughly 90 percent happen during the first division of meiosis, the cell division process that produces eggs. Failure of chromosome 22 pairs to properly exchange genetic material during this division was a contributing factor.19PubMed. The origin of trisomy 22: evidence for acrocentric chromosome-specific patterns of nondisjunction
This strong maternal bias is consistent with what is known about most autosomal aneuploidies. Eggs undergo a decades-long pause in their development and are vulnerable to errors that accumulate with age, while sperm are produced on a much shorter timeline. The finding also aligns with the observation that the risk of chromosomal abnormalities in pregnancy increases with maternal age.
Ring Chromosome 22 as a Special Case
Ring chromosome 22 deserves separate mention because it sits at the intersection of several monosomy 22 topics. A ring chromosome forms when both ends of chromosome 22 break off and the remaining piece curls into a loop, fusing the broken ends together. The material at the tips is lost, producing a partial deletion, and the ring structure itself is mechanically unstable during cell division.
Because ring chromosomes tend to get lost when cells divide, individuals with ring chromosome 22 often develop mosaic monosomy 22 over time as more and more cells lose the ring entirely. As noted in the discussion of rhabdoid tumors, this instability can have oncologic consequences when the lost chromosome carries a tumor suppressor gene like SMARCB1.20PubMed Central. Description of a new oncogenic mechanism for atypical teratoid rhabdoid tumors in patients with ring chromosome 22 Genetic counseling for families affected by ring chromosome 22 must account for both the developmental effects of the initial deletion and the ongoing risk that progressive chromosomal loss in dividing cells could lead to additional complications.
Consensus recommendations for counseling in Phelan-McDermid syndrome specifically address the ring chromosome scenario, since the mechanism of the deletion influences the recurrence risk for future pregnancies.21European Journal of Medical Genetics. Consensus recommendations on counselling in Phelan-McDermid syndrome, with special attention to recurrence risk and to ring chromosome 22 A simple deletion that arose spontaneously carries a low recurrence risk, while a ring chromosome or a parental balanced rearrangement can carry a meaningfully higher one.
Multidisciplinary Care for Partial Monosomy 22 Syndromes
Because both 22q11.2 deletion syndrome and Phelan-McDermid syndrome affect multiple organ systems and change in presentation over a person’s lifetime, no single specialist can manage either condition alone. Updated clinical practice recommendations for 22q11.2 deletion syndrome call for coordinated evaluation, surveillance, and management of the associated physical, cognitive, behavioral, and psychiatric features along with ongoing genetic counseling.22PubMed. Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome In practice, this means teams that include cardiologists, immunologists, endocrinologists, speech-language pathologists, developmental pediatricians, psychologists, and psychiatrists, with the mix shifting as the patient ages.
For Phelan-McDermid syndrome, the emphasis leans more heavily toward neurodevelopmental support, given that speech delay and autism-related behaviors are central features. Applied behavior analysis, speech therapy, occupational therapy, and physical therapy are commonly part of the management plan. Research into treatments targeting the SHANK3 pathway is ongoing but has not yet yielded approved therapies. For both syndromes, early identification and intervention tend to improve outcomes, which is a major driver behind efforts to expand prenatal and newborn screening for these deletions.