Chromosomal Disorders

Introduction to Chromosomes

Chromosomes are large, wrapped structures of DNA found in the nucleus of a cell. A human typically has 46 chromosomes (23 pairs of chromosomes) in nearly every cell of their body. However, there are instances where chromosomes do not separate properly during meiosis or mitosis, or other chromosomal abnormalities occur, leading to large-scale changes in the genome. We call these instances chromosomal disorders.

Humans have two complete sets of chromosomes; therefore, we are diploid organisms. Other organisms have more than two complete chromosome sets. Seedless watermelons, for example, are triploid organisms, meaning they have three complete chromosome sets. On the other hand, salmon are tetraploid, meaning that they have four complete chromosome sets.

Chromosome Disorders

We can describe one complete chromosome set using a variable, N. Therefore, humans with two complete chromosome sets in most cells can be denoted as 2N. An exception in humans is gametes (sperm or egg), which only have one complete chromosome set. Therefore, gametes are denoted as haploids, or N.

When an organism deviates from its normal set of chromosomes in a cell or an entire organism, it is called euploidy.

For example, a diploid organism with three or more full chromosome sets is called a polyploid. In this case, it can be denoted as 3N. In contrast, a diploid with one full chromosome set is called a monoploid, or N. Typically, monoploids and triploids in a diploid organism are lethal, meaning that they do not survive. If that individual survives to adulthood, they are sterile and cannot produce offspring.

Apart from changes to the number of chromosome sets for all chromosomes, there are instances of changes to the number of a specific chromosome, called aneuploidy.

For example, trisomy is an addition of a specific chromosome (2N + 1), while monosomy is the loss of a specific chromosome (2N - 1). In rare cases, there can be a loss of two chromosomes, called nullisomy (2N - 2), or a gain of two chromosomes, called tetrasomy (2N + 2).

Aneuploidy can also occur in sex chromosomes, which will be explored in the sections below. The causes of aneuploidy are unknown; however, the risk for aneuploidy events is higher for women trying to conceive later in life.

Extra Chromosome Disorders

As we discussed, extra chromosome disorders are an addition of a single chromosome (aneuploidy). This is often caused by an event called non-disjunction, which occurs during meiosis or mitosis (Fig. 1). During non-disjunction, chromosomes are unevenly separated into the daughter cells leading to one daughter cell having two copies of the chromosome. In contrast, the other daughter cell has zero copies of that chromosome. If the gamete with an additional chromosome is fertilized, it can lead to the fetus having 47, rather than 46, chromosomes in some or all cells.

Figure 1. Non-disjunction is where chromosomes are unevenly distributed among daughter cells.

When a single chromosome is gained, it is called trisomy and can be denoted as 2N + 1. While most trisomies will result in spontaneous abortion during pregnancy, there are three instances of autosomal trisomies where the fetus can survive until birth. These are trisomy 21 (Down syndrome), trisomy 13 (Patau syndrome), and trisomy 18 (Edward syndrome).

Down Syndrome

Down syndrome affects around 1 in every 1000 live births worldwide. Trisomy 21 is associated with physical and mental challenges due to changes in development. While the physical characteristics of trisomy 21 are unique for an individual, some common features include upward slanting eyes, a flattened bridge of the nose, and short stature. Although there are still associated co-morbidities, such as congenital heart defects and adulthood memory loss that make trisomy 21 a serious genetic abnormality, improved intervention, de-stigmatization, and care have led to greater survival and quality of life in individuals suffering from this disorder.

Patau Syndrome

It is much rarer than trisomy 21, with around 1 in every 10,000 to 22,000 live births being affected. The most serious complications of trisomy 13 are in the nervous system and cardiovascular system, which makes survival in the first few weeks after birth extremely difficult. Improvements in surgical procedures and aggressive medical treatments have led to several reports of longer survival; however, severe disability is expected in these patients.

Edward Syndrome

It affects around 1 in every 8600 live births. However, the occurrence has increased due to a trend of women having children later in life. Children born with trisomy 18 often have feeding and breathing difficulties, smaller head sizes, delayed psychomotor development, and growth impediments. Although the survival of females with Edward syndrome is higher than males, the underlying reason for this is unclear.

Missing Chromosome Disorders

Rather than the addition of a chromosome, there can be cases of a missing chromosome in some or all cells of the body, called monosomy (2N -1). An individual will have 45, rather than 46, chromosomes in monosomy.

If we recall, non-disjunction leads to a daughter cell receiving either both or no copies of a chromosome. In the case of non-disjunction during meiosis, this can lead to sperm or egg cells having no copies of a specific chromosome. The most common example of monosomy is monosomy X, also known as Turner's syndrome.

Monosomy X only affects females, as males without an X chromosome will not survive. It affects around 1 in every 2500 live female births. Females with monosomy X tend to be shorter in stature, do not naturally go through puberty, and may have other kidney or heart co-morbidities. While females with monosomy can still have children, it is often assisted with fertility treatments due to their rapid loss of eggs.

Sex Chromosome Disorders

Most biological females are XX, while most biological males are XY. However, just like how we discussed in monosomy X, aneuploidies can also occur in sex chromosomes. The six most common classifications of sex chromosome disorders are:

• XXX females
• XXY males (Klinefelter's syndrome)
• XX males
• XYY males
• XO (Turner's syndrome)
• XY females

XXX Chromosome Disorder

XXX females, or triple X syndrome, is when a female is born with an extra X chromosome in some or all of their cells. It occurs in approximately 1 in every 1000 women. However, due to the mild or absence of syndromes, it is expected that only 10% of women know about their syndrome. Since so few women know about it, they are less likely to be screened, leading to an underestimated prevalence. Females with triple X syndrome go through puberty and can conceive children naturally. However, triple X syndrome has been associated with behavioral problems, delayed development of psychomotor skills, and learning disabilities in some cases.

XXY Chromosome Disorder

XXY males, also known as Klinefelter's syndrome, occur when a male is born with an extra X chromosome in some or all cells of their body. It occurs in approximately 1 in every 500 males. While symptoms are mild, males with Klinefelter's syndrome are sterile. Often, a person with Klinefelter's syndrome may not know that they have the genetic disorder until they are trying to have children. Symptoms associated with Klinefelter's syndrome include larger stature, less body hair, breast growth, and lower sex drive.