August 2025
INTRODUCTION —
This topic describes the most common structural chromosomal anomalies, discusses their mechanisms, and gives examples of disease processes resulting from these alterations.
Chromosomal abnormalities have an important role in the pathogenesis of many hematologic disorders. Separate topics discuss these syndromes and the analysis of chromosomal structural abnormalities:
●Congenital abnormalities – (See "Congenital cytogenetic abnormalities".)
●General review of cytogenetic methods – (See "Tools for genetics and genomics: Cytogenetics and molecular genetics".)
●Cytogenetics in hematologic malignancies – (See "General aspects of cytogenetic analysis in hematologic malignancies".)
OVERVIEW —
Chromosomal abnormalities can be numerical or structural.
Abnormality of chromosome number — The normal diploid number of chromosomes in humans is 46. There are 23 pairs of chromosomes, with 22 pairs of autosomes and one pair of sex chromosomes (XX or XY). Human females have two X chromosomes (46,XX), while males have one X and one Y chromosome (46,XY). (See "Basic genetics concepts: Chromosomes and cell division", section on 'Chromosome organization'.)
All variants that change the total number of chromosomes are considered to be genome variants.
●Aneuploidy – The most common type of numerical chromosome abnormality is selective gain or loss of an individual chromosome, resulting in aneuploidy (abnormal number). As an example, trisomy 21, which causes Down syndrome, is characterized by the gain of one additional copy of chromosome 21. (See "Congenital cytogenetic abnormalities", section on 'Numeric abnormalities'.)
●Triploidy – A numerical abnormality in a cell's chromosomal number may be caused by the gain of one or more complete haploid chromosome sets (polyploid karyotype). An example is the triploid chromosomal number (eg, 69,XXY) in a partial hydatidiform mole. (See "Gestational trophoblastic disease: Pathology and genetics", section on 'Genetic mechanisms'.)
Abnormality of chromosomal structure — Structural chromosomal anomalies comprise changes that are due to one or more breaks in a chromosome. (See 'Mechanisms of chromosomal breakage' below.)
Following a break, the separated fragments are likely to undergo chromosomal rearrangements. Structural chromosomal changes can result in a displacement of chromosomal regions without any loss or duplication of genetic material (ie, balanced rearrangements) or they may be unbalanced:
●Balanced rearrangements – These are frequently inherited and are not commonly associated with phenotypic abnormalities. Two exceptions to this rule include a breakpoint that directly disrupts a gene and the displacement of chromosomal material from an X chromosome to an autosome or vice versa.
●Unbalanced rearrangements – These result in partial trisomy or monosomy for a chromosome or chromosome region and are a frequent cause of congenital abnormalities or developmental delay.
On a submicroscopic level, gene variants such as single base-pair substitutions, insertions, deletions, duplications, nucleotide repeat expansions, and inversions are usually too small to be identified by standard karyotypic analysis and require deoxyribonucleic acid (DNA) analysis for their detection. These submicroscopic mutations can be as small as a change in a single base pair, or as large as megabase stretches of DNA sequence in very large genes. (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Genetic variation'.)
MECHANISMS OF CHROMOSOMAL BREAKAGE —
Chromosomal breakage is caused by double-strand DNA breaks of endogenous or exogenous origin.
Endogenous breaks are associated with DNA replication, recombination, transcription, and repair processes, all of which require temporary double-strand DNA breaks. Permanent endogenous breaks occur in programmed cell death due to aging of the cell, cell damage, or regulation of cell numbers. Exogenous causes include exposure to irradiation and certain chemical substances, as well as other types of DNA damage.
The repair of DNA breaks occurs with high fidelity as long as the damaged area can be removed and replaced by a DNA sequence that is copied from an undamaged template. Double-strand DNA breaks, however, need repair across the damaged area on both strands and are more susceptible to errors. By altering gene structure or expression patterns, such mutations can have pathogenic consequences, including malignant transformation.
Chromosomal breakage is also a requirement for subsequent translocations, deletions, inversions, and other chromosomal rearrangements [1]. (See 'Translocations' below and 'Deletions' below and 'Inversions' below.)
TRANSLOCATIONS —
Most individuals with a balanced translocation are phenotypically unaffected. However, balanced translocations can have a causative role in both inherited and acquired genetic conditions. Phenotypic consequences may result from gene disruption, loss of a small part of the chromosome, gene dysregulation, and/or generation of fusion genes [2].
There are three types of chromosomal translocations: reciprocal, Robertsonian, and insertional (nonreciprocal).
Reciprocal translocations — Translocations are designated with the letter "t" followed by the two involved chromosomes, as in the "t(9;22)" translocation seen in chronic myeloid leukemia (CML).
●Congenital/germline – Congenital reciprocal translocations have an incidence of 0.3 to 0.5 percent [2] and originate from the breakage of two nonhomologous chromosomes that interchange their separated parts. Rarely, more than two chromosomes are involved in a reciprocal exchange of chromosome segments. When this occurs, the translocation is considered to be complex. (See "Basic genetics concepts: Chromosomes and cell division", section on 'Meiosis'.)
Normally, in a reciprocal translocation, there is no loss of genetic material. During meiosis, the normal and translocated chromosomes pair by forming a quadrivalent structure, from which one normal, one balanced, and four unbalanced products could be generated (figure 1). The unbalanced products can be subdivided into two products with correct centromere segregation and two products with incorrect centromere segregation. The latter situation, in which the gamete contains two identical centromeres, is very rare and less compatible with viability. While the theoretical expectation is that 50 percent of the gametes produced are abnormal or unbalanced, the empirical general risk of having abnormal liveborn offspring rarely exceeds 15 percent.
●Acquired/somatic – Reciprocal translocations also frequently occur as a somatic variant in hematologic malignancies and other neoplasms. The reciprocal translocation in one cell either juxtaposes two genes that are not normally near each other, inducing upregulation of one of the genes, or it causes oncogene activation by creation of a novel fusion gene. In both scenarios, clonal expansion of the affected cell directly leads to tumorigenesis. (See "Genetic abnormalities in hematologic and lymphoid malignancies".)
•Upregulated gene expression – This happens when the breakpoints are in noncoding regions. It is exemplified by the translocation of an oncogene to a gene involved in the immune response (encoding an immunoglobulin heavy or light chain or a T-cell receptor).
-One example is t(14;18), which is present in nearly 80 percent of follicular B-cell lymphomas. In this translocation, the BCL2 gene on chromosome 18 is adjoined to the immunoglobulin heavy chain gene on chromosome 14, which is constitutively expressed in B cells, leading to overexpression of BCL2 [3]. The BCL2 gene encodes proteins that block apoptosis (programmed cell death), and the resulting clone of cells escapes apoptosis and is predisposed to accumulating additional mutations.
-Another example is t(11;14), which is common in mantle cell lymphomas. This translocation juxtaposes the CCND1 gene on chromosome 11, which encodes the cell cycle regulator cyclin D1, with the immunoglobulin heavy chain locus on chromosome 14; this interferes with normal cell cycle progression [4].
•Creation of a fusion gene – This happens when the breakpoints occur within two genes, creating a hybrid gene that does not normally exist and leading to expression of a chimeric fusion protein. Genes encoding transcription factors are most frequently involved in oncogenic translocations. Their dysregulation gives rise to inappropriate target gene activation in one or more cellular pathways [5].
There are numerous examples of fusion genes. One is t(9;22), which causes fusion of the BCR gene on chromosome 22 and the ABL1 gene on chromosome 9 (figure 2). This hybrid BCR::ABL1 product is present in all patients with CML [6]. The resulting constitutively expressed oncoprotein activates multiple signal transduction cascades. (See "Chronic myeloid leukemia: Pathogenesis, clinical manifestations, and diagnosis".)
The cellular processes that determine when chromosome breaks will result in a reciprocal translocation are unknown. In cancer, instability of chromosomal number and structure are commonly observed [7], examples below.
Robertsonian translocations — Acrocentric chromosomes have an asymmetrically positioned centromere, producing one short arm and one long arm. The acrocentric human chromosomes 13, 14, 15, 21, and 22 have very short p-arms that contain only chromosomal satellites and the genetic code for ribosomal ribonucleic acids (RNAs). Their centromeres, therefore, are very close to one end of the chromosome. When the long arms of two acrocentric chromosomes merge by translocation, their short arms are lost and, depending upon the location of the breakpoints, a dicentric or monocentric fusion-chromosome is created.
Loss of the short arms of acrocentric chromosomes does not have phenotypic consequences because the lost sections do not contain unique genetic sequences. The only consequence is a balanced karyotype with 45 instead of 46 chromosomes. This is identified in approximately 1 in 1000 individuals.
However, unbalanced gametes of heterozygous carriers are common and give rise to a monosomic or trisomic fetus. Most monosomies and trisomies are lethal and spontaneously abort early in the pregnancy. Approximately 85 percent of trisomy 21 conceptuses will not survive to term. Surviving fetuses with trisomy 21, however, can be viable and affected with Down syndrome [8]. Robertsonian translocations account for a small percentage of Down syndrome overall. (See "Congenital cytogenetic abnormalities", section on 'Trisomy 21 (Down syndrome)'.)
When Down syndrome is caused by a parental Robertsonian translocation, the carrier parent typically has a fusion of the long arms of chromosomes 14 and 21 (figure 3). One of the three viable gametes will be balanced, one will be normal, and one will contain the fused chromosome [der(14;21)] as well as the unaffected chromosome 21. Normal fertilization of this gamete results in a fetus with trisomy 21. The empiric risk for a child with Down syndrome is 10 to 15 percent for a carrier mother, but only 2 percent if the father carries the Robertsonian translocation.
Insertional translocations — Insertional translocations by definition are not reciprocal and are caused by integration of a segment from a "donor" chromosome that has incurred two breakpoints into a recipient chromosome that contains only one breakpoint.
Zygotes resulting from an insertional translocation may be normal, balanced, partially trisomic, or partially monosomic. The phenotypic outcome of this anomaly, once considered rare, strongly depends upon the location of the breakpoints and on the nature of the translocated sequence.
With the advent of array comparative genomic hybridization (aCGH, also known as chromosomal microarray assay), it appears that insertional translocations (IT) are not as rare as previously believed. In 2000, the estimated incidence of microscopically visible ITs was 1/80,000, whereas subsequent studies showed them to be more common, with one estimate of 1/500 [9-13].
DELETIONS —
Deletions of chromosomal material can be any size. Macrodeletions may be detected by standard chromosomal banding techniques, whereas microdeletions are not typically visible by these methods. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Detecting cytogenetic abnormalities'.)
Macrodeletions — To microscopically see a chromosomal deletion by chromosome banding, the deletion must span at least three to five megabases (Mb). Considering that the average gene density approximates one gene per 50 kilobases (kb), it is not surprising that the loss of such a large region is likely to lead to phenotypic manifestations.
Examples include:
●Perhaps the most well-known example is Cri-du-chat syndrome, which is due to a terminal deletion of the short arm of chromosome 5 (figure 4). Congenital abnormalities in this disorder include cat-like neonatal crying, microcephaly with dysmorphic facial features, cardiac abnormalities, hypotonia, and severe intellectual disability. Even though the size of the deleted fragment differs from patient to patient, chromosomal bands 5p15.2 and 5p15.3 are always included and encompass the critical region for this phenotype [14]. (See "Congenital cytogenetic abnormalities", section on '5p deletion syndrome (cri-du-chat syndrome)'.)
●Another example of a variable size of the deleted fragment has been described in multiple myeloma. In a series of 106 patients with multiple myeloma from 2000, all but eight had a deletion of the long arm of chromosome 13, which included the 13q14 region (figure 5) [15]. (See "Multiple myeloma: Pathobiology", section on 'Cytogenetic abnormalities'.)
Microdeletions — High-resolution banding techniques and fluorescence in situ hybridization (FISH) have enabled the detection of relatively small ("micro") deletions. If the FISH probe is designed to localize to the region that is deleted on one allele, only one double signal will be present in the prometaphase chromosomal evaluation. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics".)
One example of a microdeletion syndrome is Smith-Magenis syndrome, with an incidence of 1 in 25,000 and characterized by a microdeletion of chromosome band 17p11.2. Phenotypic features include intellectual disability, a deep and hoarse voice, self-harm behavior, insomnia, short stature, and brachydactyly. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '17p11.2 deletion including RAI1 (Smith-Magenis syndrome)'.)
While most deletions span approximately 5 Mb and are cytogenetically discernible near the centromere, the remainder must be diagnosed with more refined diagnostic methods, such as FISH (image 1) [16]. The interstitial deletion in this syndrome is facilitated by the presence of regions of low-copy repeats that flank the common breakpoint regions [17]. These segments are highly homologous, which makes them prone to unequal crossing over in meiosis I. During unequal crossing over, two nonsister chromatids recombine at an incorrect location due to inappropriate alignment of highly homologous DNA sequences. Thus, one of the chromatids acquires a duplication of the intervening sequence, while the corresponding segment is deleted on the other chromatid (figure 6). This is called nonallelic homologous recombination (NAHR) and is the basis of most microdeletion/microduplication syndromes. (See "Microdeletion syndromes (chromosomes 1 to 11)" and "Microdeletion syndromes (chromosomes 12 to 22)".)
Another example of a microdeletion syndrome caused by NAHR is Williams syndrome (or Williams-Beuren syndrome, WBS). Phenotypic features include cardiovascular disease (most frequently supravalvular aortic stenosis), distinctive faces with full lips and periorbital fullness, and an unusual and intellectual disability with relative cognitive strength in verbal abilities. Over 99 percent of individuals with Williams syndrome have a contiguous gene deletion that encompasses the elastin (ELN) gene at 7q11.23. Approximately 95 percent of individuals affected with WBS have a 1.55 Mb microdeletion, while the other 5 percent have a larger 1.84 Mb microdeletion. (See "Microdeletion syndromes (chromosomes 1 to 11)", section on '7q11.23 deletion syndrome (Williams syndrome)'.)
Homologous recombination during mitosis is both rare and abnormal. Nevertheless, unequal crossing over can also occur in mitotic division and leads to unequal sister chromatid exchange. The basic mechanism of misalignment between repeat sequences is the same as in meiosis. This abnormal event in mitosis, however, results in a somatic mutation and can predispose to cancer if the deleted sequence contains (or is part of) a tumor suppressor gene.
A subset of hypereosinophilic syndromes has a novel FIP1L1-PDGFRA fusion due to a large interstitial deletion on chromosome 4q12. This results in a fusion protein with constitutive tyrosine kinase activity, eosinophilic proliferation, and end-organ damage. In patients with this fusion, the disease frequently responds to the tyrosine kinase inhibitor imatinib mesylate. Diagnosis of this fusion protein can be made by demonstrating the loss of the CHIC2 gene within the deleted region by FISH, or by PCR demonstrating the presence of a fusion transcript [18,19]. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)
INVERSIONS —
Chromosomal inversions are characterized by two breaks on the same chromosome, rotation of the intervening segment by 180 degrees, followed by chromosomal reintegration of the intervening segment in an "upside down" position.
Inversions can be subclassified based on the location of their breaks:
●Breakpoints on a single chromosome arm define paracentric inversions. (See 'Paracentric inversions' below.)
●Breakpoints on both sides of the centromere (both arms of the same chromosome) define pericentric inversions.
Carriers of chromosome inversions typically are phenotypically unaffected. However, complications may arise during reproduction because at meiosis, the inverted chromosome must pair with the noninverted sister chromatid, forming a loop. If crossing-over occurs, unbalanced or abnormal gametes may result. (See "Basic genetics concepts: Chromosomes and cell division", section on 'Meiosis'.)
Paracentric inversions — Paracentric inversions (figure 7) are relatively rare but have been observed in all 23 autosomes and both sex chromosomes [20]. The chromosomes in individuals with a paracentric inversion are more likely to be ascertained because of infertility or repeated miscarriages in the affected individual rather than phenotypic abnormalities in their offspring. The risk of an affected child is generally very small, due to one of the following mechanisms:
●The transmitted chromosome is normal.
●The transmitted chromosome is inverted and compatible with life, as in the parent.
●After recombination in the inverted region, the transmitted chromosome becomes acentric or dicentric.
Gametes with acentric fragments or dicentric chromosomes are not typically viable. In general, inherited paracentric inversions are innocuous. However, there are rare reported cases of offspring with phenotypic abnormalities [20].
Pericentric inversions — A pericentric inversion (figure 8) changes the banding pattern of the affected chromosome and may change the position of the centromere as well.
The region distal to the inverted segment of the recombinant chromosome, closer to the telomere, may be partially duplicated or deleted [21]. Larger segments are more susceptible to crossing over in meiosis I, since generally at least one cross-over takes place per chromosome arm. Hence, larger pericentric inversions are associated with an increased risk of phenotypic anomalies in offspring because the duplicated or deleted segments will be smaller and more likely compatible with life.
In cells with malignant transformation due to somatic mutation, reciprocal translocations and deletions are much more commonly identified than inversions. As a class, inversions are encountered in only 2 percent of all chromosome aberrations seen in cancers with one or multiple chromosome anomalies.
SUMMARY
●Definitions – Chromosomal aberrations are due to either numerical abnormalities or structural variants.
•Numerical – Polyploidy is the gain of one or more complete sets of haploid chromosomes (eg, 69,XXY in a partial hydatidiform mole). Aneuploidy, the gain or loss of an individual chromosome, is more common. Trisomy 21, which causes Down syndrome, is characterized by the gain of one additional copy of chromosome 21. Polyploidy and aneuploidy represent genome mutations; these are by definition detrimental. (See 'Abnormality of chromosome number' above.)
•Structural – Structural chromosomal anomalies are due to one or more breaks in a chromosome. Structural chromosomal changes can be balanced (without any loss or gain of genetic material, and typically phenotypically normal) or unbalanced (with loss and gain of genetic material, and typically phenotypically abnormal). (See 'Abnormality of chromosomal structure' above.)
●Chromosomal translocations – Chromosomal translocations are a type of structural anomaly. There are three types: reciprocal, Robertsonian, and insertional (nonreciprocal).
•Reciprocal – Congenital reciprocal translocations can result in gametes with unbalanced genetic material, although most viable offspring carry normal or balanced chromosomes. Reciprocal translocations frequently occur as a somatic mutation in hematologic and other malignancies. Transcription factor genes are most frequently involved in oncogenic translocation. (See 'Reciprocal translocations' above.)
•Robertsonian – Robertsonian translocations involve acrocentric chromosomes with short p-arms that can be lost in translocation of the long arms, resulting in a balanced karyotype with 45, rather than 46, chromosomes and a normal phenotype. However, unbalanced gametes of heterozygous carriers are common and give rise to a monosomic or trisomic fetus. Trisomy 21 can be caused by a parent with a Robertsonian translocation. (See 'Robertsonian translocations' above.)
•Insertional – Insertional translocations are caused by integration of a segment from a "donor" chromosome that has incurred two breakpoints into a recipient chromosome that contains only one breakpoint. The resulting zygotes may be normal, balanced, partially trisomic, or partially monosomic. (See 'Insertional translocations' above.)
●Deletions – Deletions involve loss of chromosomal material.
•Macrodeletions, which can be seen microscopically, span at least three to five megabases (Mb) and therefore are likely to have phenotypic manifestations. Examples are found in patients with Cri-du-chat syndrome and some patients with multiple myeloma. (See 'Macrodeletions' above.)
•Microdeletions are smaller deletions that can be detected by high-resolution banding techniques and fluorescence in situ hybridization (FISH), as well as by array comparative genomic hybridization (aCGH). Most microdeletion or microduplication syndromes result from nonallelic homologous recombination (NAHR), in which highly homologous repeat DNA sequences lead to unequal crossing over and erroneous recombination in meiosis I. Similarly, unequal crossing over in mitotic division can result in a somatic mutation, which can predispose to cancer if the deleted sequence contains a tumor suppressor gene. (See 'Microdeletions' above.)
●Inversions – Inversions, in which a segment of the chromosome is rotated 180 degrees, can be paracentric, involving one chromosome arm, or pericentric, involving both arms of the chromosome. Chromosomes with inversions are likely to be recognized at the time of evaluation for infertility or repeated miscarriages, or they may be found incidentally during prenatal diagnosis. A pericentric inversion causes changes in the banding pattern of the affected chromosome and may change the position of the centromere. Larger pericentric inversions are associated with an increased risk of phenotypic anomalies because the duplicated or deleted segments will be smaller and more likely compatible with life. (See 'Inversions' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Athena M Cherry, PhD, who contributed to earlier versions of this topic review.
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