5 Chromosomal Disorders

A chromosomal disorder, anomaly, aberration, or mutation is a missing, extra, or irregular portion of chromosomal DNA. It can be from a typical number of chromosomes or a structural abnormality in one or more chromosomes.

5.1 Aberrations

Chromosomal aberrations are disruptions in the normal chromosomal content of a cell and are a major cause of genetic conditions in humans, such as Down syndrome, although most aberrations have little to no effect. Some chromosome abnormalities do not cause disease in carriers, such as translocations, or chromosomal inversions, although they may lead to a higher chance of bearing a child with a chromosome disorder. Abnormal numbers of chromosomes or chromosome sets, called aneuploidy, may be lethal or may give rise to genetic disorders. Genetic counseling is offered for families that may carry a chromosome rearrangement.

5.2 Numerical abnormalities

Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example when an individual either is missing a chromosome from a pair (monosomy) or has more than two chromosomes of a pair (trisomy, tetrasomy, etc.). In the strict sense, a chromosome complement having a number of chromosomes other than 46 (in humans) is considered heteroploid while an exact multiple of the haploid chromosome complement is considered euploid. Thus, a cell with any number of complete chromosome sets is called a euploid cell. An extra or missing chromosome is a common cause of genetic disorders, including some human birth defects. Some cancer cells also have abnormal numbers of chromosomes. About 68% of human solid tumors are aneuploid. Aneuploidy originates during cell division when the chromosomes do not separate properly between the two cells.

Table 5.1: Terminology and examples of heteroploidy in humans.
Number of chromosomes	Name	Description
1	Monosomy	Monosomy refers to lack of one chromosome of the normal complement. Partial monosomy can occur in unbalanced translocations or deletions, in which only a portion of the chromosome is present in a single copy (see deletion (genetics)). Monosomy of the sex chromosomes (45,X) causes Turner syndrome.
2	Disomy	Disomy is the presence of two copies of a chromosome. For organisms such as humans that have two copies of each chromosome (those that are diploid), it is the normal condition. For organisms that normally have three or more copies of each chromosome (those that are triploid or above), disomy is an aneuploid chromosome complement. In uniparental disomy, both copies of a chromosome come from the same parent (with no contribution from the other parent).
3	Trisomy	Trisomy refers to the presence of three copies, instead of the normal two, of a particular chromosome. The presence of an extra chromosome 21, which is found in Down syndrome, is called trisomy 21. Trisomy 18 and Trisomy 13, known as Edwards syndrome and Patau syndrome, respectively, are the two other autosomal trisomies recognized in live-born humans. Trisomy of the sex chromosomes is also possible, for example (47,XXX), (47,XXY), and (47,XYY).
4/5	Tetrasomy/pentasomy	Tetrasomy and pentasomy are the presence of four or five copies of a chromosome, respectively. Although rarely seen with autosomes, sex chromosome tetrasomy and pentasomy have been reported in humans, including XXXX, XXYY, XXXXX, XXXXY, and XYYYY.

An example of trisomy in humans is Down syndrome, which is a developmental disorder caused by an extra copy of chromosome 21; the disorder is therefore also called trisomy 21. Having an extra copy of this chromosome means that individuals have three copies of each of its genes instead of two, making it difficult for cells to properly control how much protein is made. Producing too much or too little protein can have serious consequences. Genes on chromosome 21 that specifically contribute to the various symptoms of Down syndrome are now being identified. The frequency of Trisomy 21 has been determined to be a function of advanced maternal age.

An example of monosomy is Turner syndrome, where the individual is born with only one sex chromosome, an X.

Other examples include:

Cri du chat, which is caused by the deletion of part of the short arm of chromosome 5. “Cri du chat” means “cry of the cat” in French; the condition was so-named because affected babies make high-pitched cries that sound like those of a cat. Affected individuals have wide-set eyes, a small head and jaw, moderate to severe mental health problems, and are very short.
Edwards syndrome, or trisomy-18, the second most common trisomy. Symptoms include motor retardation, developmental disability and numerous congenital anomalies causing serious health problems. Ninety percent of those affected die in infancy. They have characteristic clenched hands and overlapping fingers.
Isodicentric 15, also called idic(15), partial tetrasomy 15q, or inverted duplication 15 (inv dup 15).
Jacobsen syndrome, which is very rare. It is also called the terminal 11q deletion disorder. Those affected have normal intelligence or mild developmental disability, with poor expressive language skills. Most have a bleeding disorder called Paris-Trousseau syndrome.
Klinefelter syndrome (XXY). Men with Klinefelter syndrome are usually sterile and tend to be taller and have longer arms and legs than their peers. Boys with the syndrome are often shy and quiet and have a higher incidence of speech delay and dyslexia. Without testosterone treatment, some may develop gynecomastia during puberty.
Patau Syndrome, also called D-Syndrome or trisomy-13. Symptoms are somewhat similar to those of trisomy-18, without the characteristic folded hand.
Small supernumerary marker chromosome. This means there is an extra, abnormal chromosome. Features depend on the origin of the extra genetic material. Cat-eye syndrome and isodicentric chromosome 15 syndrome (or Idic15) are both caused by a supernumerary marker chromosome, as is Pallister–Killian syndrome.
Triple-X syndrome (XXX). XXX girls tend to be tall and thin and have a higher incidence of dyslexia.
Wolf–Hirschhorn syndrome, which is caused by partial deletion of the short arm of chromosome 4. It is characterized by growth retardation, delayed motor skills development, “Greek Helmet” facial features, and mild to profound mental health problems.
XYY syndrome. XYY boys are usually taller than their siblings. Like XXY boys and XXX girls, they are more likely to have learning difficulties.

Chromosome abnormalities are detected in 1 of 160 live human births. Most cases of aneuploidy in the germline result in miscarriage and the most common extra autosomal chromosomes among live births are 21, 18, and 13.

Most cells in the human body have 23 pairs of chromosomes, or a total of 46 chromosomes. (The sperm and egg, or gametes, each have 23 unpaired chromosomes, and red blood cells have no nucleus and no chromosomes). One copy of each pair is inherited from the mother and the other copy is inherited from the father. The first 22 pairs of chromosomes (called autosomes) are numbered from 1 to 22, from largest to smallest. The 23rd pair of chromosomes are the sex chromosomes. Normal females have two X chromosomes, while normal males have one X chromosome and one Y chromosome. The characteristics of the chromosomes in a cell as they are seen under a light microscope are called the karyotype.

During meiosis, when germ cells divide to create sperm and egg (gametes), each half should have the same number of chromosomes. But sometimes, the whole pair of chromosomes will end up in one gamete, and the other gamete will not get that chromosome at all.

Most embryos cannot survive with a missing or extra autosome (numbered chromosome) and are spontaneously aborted. The most frequent aneuploidy in humans is trisomy 16, although fetuses affected with the full version of this chromosome abnormality do not survive to term (it is possible for surviving individuals to have the mosaic form, where trisomy 16 exists in some cells but not all). The most common aneuploidy that infants can survive with is trisomy 21, which is found in Down syndrome, affecting 1 in 800 births. Trisomy 18 (Edwards syndrome) affects 1 in 6,000 births, and trisomy 13 (Patau syndrome) affects 1 in 10,000 births. 10% of infants with trisomy 18 or 13 reach 1 year of age.

Changes in chromosome number may not necessarily be present in all cells in an individual. When aneuploidy is detected in a fraction of cells in an individual, it is called chromosomal mosaicism. In general, individuals who are mosaic for a chromosomal aneuploidy tend to have a less severe form of the syndrome compared to those with full trisomy. For many of the autosomal trisomies, only mosaic cases survive to term. However, mitotic aneuploidy may be more common than previously recognized in somatic tissues, and aneuploidy is a characteristic of many types of tumorigenesis (see below).

5.2.1 Mechanisms

Nondisjunction usually occurs as the result of a weakened mitotic checkpoint, as these checkpoints tend to arrest or delay cell division until all components of the cell are ready to enter the next phase. If a checkpoint is weakened, the cell may fail to ‘notice’ that a chromosome pair is not lined up on the mitotic plate, for example. In such a case, most chromosomes would separate normally (with one chromatid ending up in each cell), while others could fail to separate at all. This would generate a daughter cell lacking a copy and a daughter cell with an extra copy.

Completely inactive mitotic checkpoints may cause nondisjunction at multiple chromosomes, possibly all. Such a scenario could result in each daughter cell possessing a disjoint set of genetic material.

5.2.2 Diagnosis

Germline aneuploidy is typically detected through karyotyping, a process in which a sample of cells is fixed and stained to create the typical light and dark chromosomal banding pattern and a picture of the chromosomes is analyzed. Other techniques include fluorescence in situ hybridization (FISH), quantitative PCR of short tandem repeats, quantitative fluorescence PCR (QF-PCR), quantitative PCR dosage analysis, Quantitative Mass Spectrometry of Single Nucleotide Polymorphisms, and comparative genomic hybridization (CGH).

These tests can also be performed prenatally to detect aneuploidy in a pregnancy, through either amniocentesis or chorionic villus sampling Pregnant women of 35 years or older are offered prenatal testing because the chance of chromosomal aneuploidy increases as the mother’s age increases.

Recent advances have allowed for less invasive testing methods based on the presence of fetal genetic material in maternal blood.

5.3 Structural abnormalities

When the chromosome’s structure is altered, this can take several forms:

Deletions: A portion of the chromosome is missing or deleted. Known disorders in humans include Wolf-Hirschhorn syndrome, which is caused by partial deletion of the short arm of chromosome 4; and Jacobsen syndrome, also called the terminal 11q deletion disorder.
Duplications: A portion of the chromosome is duplicated, resulting in extra genetic material. Known human disorders include Charcot-Marie-Tooth disease type 1A, which may be caused by duplication of the gene encoding peripheral myelin protein 22 (PMP22) on chromosome 17.
Translocations: A portion of one chromosome is transferred to another chromosome. There are two main types of translocations:
- Reciprocal translocation: Segments from two different chromosomes have been exchanged.
- Robertsonian translocation: An entire chromosome has attached to another at the centromere - in humans these only occur with chromosomes 13, 14, 15, 21, and 22.
Inversions: A portion of the chromosome has broken off, turned upside down, and reattached, therefore the genetic material is inverted.
Insertions: A portion of one chromosome has been deleted from its normal place and inserted into another chromosome.
Rings: A portion of a chromosome has broken off and formed a circle or ring. This can happen with or without loss of genetic material.
Isochromosome: Formed by the mirror image copy of a chromosome segment including the centromere.

Chromosome instability syndromes are a group of disorders characterized by chromosomal instability and breakage. They often lead to an increased tendency to develop certain types of malignancies.

Most chromosome abnormalities occur as an accident in the egg cell or sperm, and therefore the anomaly is present in every cell of the body. Some anomalies, however, can happen after conception, resulting in mosaicism (where some cells have the anomaly and some do not). Chromosome anomalies can be inherited from a parent or be “de novo”. This is why chromosome studies are often performed on parents when a child is found to have an anomaly. If the parents do not possess the abnormality it was not initially inherited; however it may be transmitted to subsequent generations.

5.4 Acquired chromosomal abnormalities

Most cancers, if not all, involve chromosome abnormalities, with either the formation of hybrid genes and fusion proteins, deregulation of genes and overexpression of proteins, or loss of tumor suppressor genes.