Structural rearrangements result from chromosome breakage, recombination, or exchange, followed by reconstitution into an abnormal combination. Whereas rearrangements can take place in many ways, they are collectively less common than aneuploidy; overall, structural abnormalities are present in ~1 in 375 newborns (see Fig. 1). Like numeric abnormalities, structural rearrangements may be present in all cells of a person or in mosaic form.
Fig1. Incidence of chromosome abnormalities in newborn surveys, based on chromosome analysis of over 68,000 newborns. (Data summarized from Hsu LyF: Prenatal diagnosis of chromosomal abnormalities through amniocentesis. In Milunsky A, editor: Genetic disorders and the fetus, ed 4, Baltimore, 1998, Johns Hopkins University Press, pp 179– 248.)
Structural rearrangements are classified as balanced if the genome has the normal complement of chromosomal material or unbalanced if material is additional or missing. Clearly, these designations depend on the resolution of the method(s) used to analyze a particular rearrangement (see Fig. 2); some that appear balanced at the level of high- resolution banding, for example, may be seen as unbalanced when studied with chromosomal microarrays or by DNA sequence analysis. Chromosome rearrangements can be stable, capable of passing through mitotic and meiotic cell divisions unaltered, whereas others are unstable. Some of the more common types of structural rearrangements observed in human chromosomes are illustrated schematically in Fig3.
Fig2. Spectrum of resolution in chromosome and genome analysis. The typical resolution and primary methods used to detect them are given for various technologic approaches used routinely in chromosome and genome analysis. See text for details and specific examples. (Redrawn from Trost B, Loureiro LO, Scherer SW: Discovery of genomic variation across a generation. Hum Mol Genet 30(2):R174–R186, 2021.)
Fig3. Structural rearrangements of chromosomes, described in the text. (A) Terminal and interstitial deletions, each generating an acentric fragment that is typically lost. (B) Duplication of a chromosomal segment, leading to partial trisomy. (C) Ring chromosome with two acentric fragments. (D) Generation of an isochromosome for the long arm of a chromosome. (E) Robertsonian translocation between two acrocentric chromosomes, frequently leading to a pseudodicentric chromosome. Robertsonian translocations are nonreciprocal, and the short arms of the acrocentrics are lost. (F) Translocation between two chromosomes, with reciprocal exchange of the translocated segments.
Unbalanced Rearrangements
Unbalanced rearrangements are detected in ~1 in 1600 live births (see Fig. 1); the phenotype is likely to be abnormal because of deletion or duplication of multiple genes, or (in some cases) both. Duplication of part of a chromosome leads to partial trisomy for the genes within that segment; deletion leads to partial monosomy. As a general concept, any change that disturbs normal gene dosage balance can result in abnormal development; a broad range of phenotypes can result, depending on the nature of the specific genes whose dosage is altered in a particular case.
Large structural rearrangements involving imbalance of at least a few megabases can be detected at the level of routine chromosome banding. Detection of smaller changes, however, generally requires higher resolution analysis, involving FISH or chromosomal microarray analysis.
Deletions and Duplications. Deletions involve loss of a chromosome segment, resulting in chromosome imbalance (see Fig. 3). A carrier of a chromosomal deletion (with one normal homologue and one deleted homologue) is monosomic for the genetic information on the corresponding segment of the normal homologue. The clinical consequences generally reflect haploinsufficiency (literally, the inability of a single copy of the genetic material to carry out the functions normally performed by two copies), and, where examined, their severity reflects the size of the deleted segment and the number and function of the specific genes that are deleted. Cytogenetically visible autosomal deletions have an incidence of ~1 in 7000 live births. Smaller, submicroscopic deletions detected by CMA or WGS are much more common, but as mentioned earlier, the clinical significance of many such variants has yet to be determined.
A deletion may occur at the end of a chromosome (terminal) or within a chromosome arm (interstitial). Deletions may originate simply from chromosome breakage and loss of the acentric segment. Numerous deletions have been identified in the course of prenatal diagnosis or in the investigation of dysmorphic patients or those with intellectual disability.
In general, duplication appears to be less harmful than deletion. However, duplication in a gamete results in chromosomal imbalance (i.e., partial trisomy), and the chromosome breaks that generate it may disrupt genes, and can lead to some phenotypic abnormality.
Marker and Ring Chromosomes. Very small, unidentified chromosomes, called marker chromosomes, are occasionally seen in chromosome preparations, frequently in a mosaic state. They are usually in addition to the normal chromosome complement and are thus also referred to as supernumerary chromosomes or extra structurally abnormal chromosomes. The prenatal frequency of de novo supernumerary marker chromosomes has been estimated to be ~1 in 2500 pregnancies. Because of their small and indistinctive appearance, higher resolution genome analysis (e.g., FISH and/or CMA) is usually required for precise identification.
Larger marker chromosomes contain genomic mate rial from one or both chromosome arms, creating an imbalance for whatever genes are present. Depending on the origin of the marker chromosome, the risk for a fetal abnormality can range from very low to 100%. For rea sons not fully understood, a relatively high proportion of such markers derive from chromosome 15 and from the sex chromosomes.
Many marker chromosomes lack telomeres and are ring chromosomes that are formed when a chromo some undergoes two breaks, and the broken ends of the chromosome reunite in a ring structure (see Fig. 3). Some rings experience difficulties at mitosis, when the two sister chromatids become tangled in their attempt to disjoin at anaphase. There may be breakage of the ring followed by fusion, and larger and smaller rings may thus be generated. Because of this mitotic instability it is not uncommon for ring chromosomes to be found in only a proportion of cells.
Isochromosomes. An isochromosome is a chromosome in which one arm is missing and the other duplicated in a mirror- image fashion (see Fig. 3). A person with 46 chromosomes carrying an isochromosome therefore has a single copy of the genetic mate rial of one arm (partial monosomy) and three copies of the genetic material of the other arm (partial trisomy). Although isochromosomes for a number of autosomes have been described, the most common isochromosome involves the long arm of the X chromosome—designated i(X)(q10)—in a proportion of individuals with Turner syndrome. Isochromosomes are also frequently seen in karyotypes of both solid tumors and hematologic malignant neoplasms.
Dicentric Chromosomes. A dicentric chromosome is a rare type of abnormal chromosome in which two chromosome segments, each with a centromere, fuse end to end. Dicentric chromosomes, despite their two centromeres, can be mitotically stable if one of the two centromeres is inactivated epigenetically or if the two centromeres always coordinate their movement to one or the other pole during anaphase. Such chromosomes are formally called pseudodicentric. The most common pseudodicentrics involve the sex chromosomes or the acrocentric chromosomes (so- called Robertsonian trans locations).
Balanced Rearrangements
Balanced chromosomal rearrangements are found in as many as 1 in 500 individuals (see Fig. 1) and do not usually lead to a phenotypic effect because all the genomic material is present, even though it is arranged differently (see Fig. 3). As noted earlier, it is important to distinguish here between truly balanced rearrangements and those that appear balanced cytogenetically but are really unbalanced at the molecular level. Because of the high frequency of common copy number variants around the genome, collectively adding up to differences of many megabases between genomes of unrelated individuals, the concept of what is balanced or unbalanced is subject to ongoing investigation and continual refinement.
Even when structural rearrangements are truly balanced, they can pose a threat to the subsequent generation because carriers are likely to produce unbalanced gametes and therefore have an increased risk for abnormal offspring with unbalanced karyotypes. There is also a possibility that one of the chromosome breaks will disrupt a gene, leading to a pathogenic variant. Especially with the use of WGS to examine the nature of apparently balanced rearrangements in patients who present with significant phenotypes, this is an increasingly well- documented cause of disorders in carriers of balanced translocations; such translocations can be a useful clue to the identification of the gene responsible for a particular genetic disorder.
Translocations. Translocation involves the movement of chromosome segments between two chromosomes. There are two main types: reciprocal and nonreciprocal.
Reciprocal Translocations. This type of rearrangement results from breakage or recombination involving nonhomologous chromosomes, with reciprocal exchange of the broken- off or recombined segments (see Fig. 3). Usually, only two chromosomes are involved, and because the exchange is reciprocal, the total chromosome number and content is unchanged. Such trans locations are usually without phenotypic effect; however, like other balanced structural rearrangements, they are associated with a high risk for unbalanced gametes and abnormal progeny. They come to attention either during prenatal diagnosis or when the parents of a clinically abnormal child with an unbalanced translocation are karyotyped. Balanced translocations are more common in couples who have had two or more spontaneous pregnancy losses and in infertile males than in the general population.
Translocations present challenges for the process of chromosome pairing and homologous recombination during meiosis. When the chromosomes of a carrier of a balanced reciprocal translocation pair at meiosis (Fig. 4), they must form a quadrivalent to ensure proper alignment of homologous sequences (rather than the typical bivalents seen with normal chromosomes). In typical segregation, two of the four chromosomes in the quadrivalent go to each pole at ana phase; however, the chromosomes can segregate from this configuration in several ways, depending on which chromosomes go to which pole. Alternate segregation, the usual type of meiotic segregation, produces balanced gametes that have either a normal chromosome complement or contain the two reciprocal chromosomes. Other segregation patterns, however, always yield unbalanced gametes (see Fig. 4).
Fig4. (A) Diagram illustrating a balanced translocation between two chromosomes, involving a reciprocal exchange between the distal long arms of chromosomes A and B. (B) Formation of a quadrivalent in meiosis is necessary to align the homologous segments of the two derivative chromosomes and their normal homologues. (C) Patterns of segregation in a carrier of the translocation, leading to either balanced or unbalanced gametes, shown at the bottom. Adjacent- 1 segregation (in red, top chromosomes to one gamete, bottom chromosomes to the other) leads only to unbalanced gametes. Adjacent- 2 segregation (in green, left chromosomes to one gamete, right chromosomes to the other) also leads only to unbalanced gametes. Only alternate segregation (in gray, upper left/ lower right chromosomes to one gamete, lower left/ upper right to the other) can lead to balanced gametes.
Robertsonian Translocations. Robertsonian trans locations are the most common type of chromosome rearrangement observed in our species. They involve two acrocentric chromosomes that fuse near the centromere region with loss of the short arms (see Fig. 3). Such translocations are nonreciprocal, and the resulting karyotype has only 45 chromosomes, including the translocation chromosome, which in effect is made up of the long arms of two acrocentric chromosomes. Because, as noted earlier, the short arms of all five pairs of acrocentric chromosomes consist largely of various classes of satellite DNA, as well as hundreds of copies of ribosomal RNA genes, loss of the short arms of two acrocentric chromosomes is not deleterious; thus the karyotype is considered to be balanced, despite having only 45 chromosomes. Robertsonian translocations are typically, although not always, pseudodicentric (see Fig. 3), reflecting the location of the breakpoint on each acrocentric chromosome.
Although Robertsonian translocations can involve all combinations of the acrocentric chromosomes, two—designated rob(13;14)(q10;q10) and rob(14;21) (q10;q10)—are relatively common. The translocation involving 13q and 14q is found in ~1 in 1300 persons and is thus by far the most common chromosome rearrangement in our species. Rare individuals with two copies of the same type of Robertsonian translocation have been described; these phenotypically normal individuals have only 44 chromosomes and lack any normal copies of the acrocentrics involved, replaced by two copies of the translocation.
Although a carrier of a Robertsonian translocation does not present with any obvious clinical phenotype, there is a risk for unbalanced gametes and, therefore, for unbalanced offspring. The risk for unbalanced off spring varies according to the particular Robertsonian translocation and the sex of the carrier parent; carrier females in general have a higher risk for transmitting the translocation to an affected child. The chief clinical importance of this type of translocation is that carriers of a Robertsonian translocation involving chromosome 21 are at risk for producing a child with translocation Down syndrome.
Insertions. An insertion is another type of non-reciprocal translocation that occurs when a segment removed from one chromosome is inserted into a different chromosome or in a different location within the same chromosome, either in its usual orientation with respect to the centromere or inverted. Because they require three chromosome breaks, insertions are relatively rare. Segregation in an insertion carrier can produce offspring with duplication or deletion of the inserted segment, as well as normal offspring and balanced carriers. The average risk for producing an affected child can be up to 50%, and prenatal diagnosis is therefore indicated.
Inversions. An inversion occurs when a single chromo some undergoes two breaks and is reconstituted with the segment between the breaks inverted. Inversions are of two types (Fig. 5): paracentric, in which both breaks occur in one arm (Greek para, beside the centromere); and pericentric, in which there is a break in each arm (Greek peri, around the centromere). Pericentric inversions can be easier to identify cytogenetically when they change the proportion of the chromosome arms as well as the banding pattern.
Fig5. Crossing over within inversion loops formed at meiosis I in carriers of a chromosome with segment B- C inverted. (A) Paracentric inversion. Gametes formed after the second meiotic division usually contain either a normal (A- B- C- D) or a balanced (A- C- B- D) copy of the chromosome because the acentric and dicentric products of the crossover are inviable. (B) Pericentric inversion. Gametes formed after the second meiotic division may be balanced (normal or inverted) or unbalanced. Unbalanced gametes contain a copy of the chromosome with a duplication or a deletion of the material flanking the inverted segment (A- B- C- A or D- B- C- D).
An inversion does not usually cause an abnormal phenotype in carriers because it is a balanced rearrangement. Its medical significance is for the progeny; a carrier of either type of inversion is at risk for producing unbalanced gametes and offspring. When an inversion is present, a loop needs to form to allow alignment and pairing of homologous segments of the normal and inverted chromosomes in meiosis I (see Fig. 5). When recombination occurs within the loop, gametes with balanced chromosome complements (either normal or with the inversion) and gametes with unbalanced complements are formed, depending on the location of recombination events. When the inversion is paracentric, the unbalanced recombinant chromosomes are acentric or dicentric and typically do not lead to viable offspring (see Fig. 5); thus the risk that a carrier of a paracentric inversion will have a liveborn child with an abnormal karyotype is very low.
A pericentric inversion, on the other hand, can lead to the production of unbalanced gametes with both duplication and deletion of chromosome segments (see Fig. 5). The duplicated and deleted segments are those distal to the inversion. Overall, the risk for the child of a carrier of a pericentric inversion to have an unbalanced karyotype is estimated to be 5% to 10%. Each pericentric inversion, however, is associated with a particular risk, typically reflecting the size and content of the duplicated and deficient segments.
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