Aneuploidy

Aneuploidy definition

Before we define what aneuploidy is, let's go through a quick crash course on what genes are and what genetic mutations entail!

Genes overview

Genes are composed of deoxyribonucleic acid (DNA) and are contained in intranuclear cell organelles called chromosomes. Each chromosome contains a linear molecule of DNA folded several times on itself, as well as ribonucleic acid (RNA) and proteins.

Figure 1. Chromosome.

Since all genes exist in pairs, all chromosomes must, of course, be paired. The members of each pair of genes are called alleles, and of each pair of chromosomes, homologs. The conventional representation of the constitution of homologs within the nucleus is defined as a cell karyotype.

• If at a particular genetic locus, the alleles are identical, that locus is defined as homozygous.

• If the alleles are not identical, the locus is heterozygous.

Except for gametes, all normal human cells contain 23 pairs of chromosomes, 46 in all. One such pair determines, in part, the primary sex of the embryonic gonads.

These sex chromosomes are called X and Y chromosomes and are not genetically homologous except in some areas. Females have 23 X chromosomes, while males have one X chromosome and one Y chromosome. The remaining 22 pairs are called autosomes and determine non-sex-linked (somatic) traits.

During most of the cell cycle, chromosomes are dispersed in the nucleus and cannot be morphologically identified. Only when the cell divides do chromosomes become morphologically evident.

Now that we have this breakdown out of the way let's hop back to the original track we were on. So, what happens if somehow a mess occurs in the number of chromosomes or the overall process? What genetic mutations occur?

Unfortunately, if there is aneuploidy in a gamete, as a result of an error in chromosomal division (could be either non-disjunction or delay during anaphase) during myosis, all the cells of the fertilized embryo will be affected.

Types of aneuploidy

There are two types of aneuploidy:

• Monosomy: loss of one chromosome.

  • Monosomy 21 is a chromosomal abnormality characterized by the loss of variable portions of a segment of the long arm of chromosome 21, which carries an increased risk of developing congenital defects, developmental delay, and cognitive impairment.

  • If an egg that has not received any chromosome 21 is fertilized, the zygote will contain only one copy: it will be monosomal for chromosome 21. Amongst our species, no monosomy involving somatic chromosomes gives rise to viable embryos.

  • An example of a syndrome associated with Monosomy 21 is Turner syndrome. This is due to the deletion of an entire X chromosome.

    • Consequently, there will be the birth of X0 females who do not normally mature sexually and who often show malformations to the skeleton or internal organs.

Turnery Syndrome - Monosomy21

• Trisomy: a gain of one chromosome.

  • If, during the formation of a human egg cell, both members of chromosome 21 pair at anaphase move to the same pole, the resulting gametes will contain zero or two chromosomes 21.

  • If, instead, an egg cell with two chromosomes 21 is fertilized from a normal sperm, the resulting zygote will contain three copies: that is, it will be trisomic for chromosome 21.

  • Trisomy 21 can be due to two distinct reasons: a meiotic nondisjunction, or a translocation of a large part of chromosome 21, usually to chromosome 14.

  • Two other trisomies are known, Patau syndrome (trisomy 13) and Edwards (trisomy 18). In both cases, almost none of the few babies born exceed the first few months of life.

Figure 3. Trisomy21, Down Syndrome.

Aneuploidy genetic disorders

As we learned above, aneuploidy is defined as chromosomal anomalies characterized by alterations in the number of chromosomes, that is, by a greater or lesser number of chromosomes than the standard number. With this genetic disorder comes syndromes:

• TRISOMY 21: It is caused by the presence of an extra copy of chromosome 21 and is also known as Down's Syndrome. It is the most common genetic cause of mental retardation. Trisomy 21 is estimated to be present in 1/700 births.
• TRISOMY 18: It is caused by the presence of an extra copy of chromosome 18. Also known as Edwards Syndrome, it is associated with high abortion. It causes severe mental retardation. Infants with trisomy 18 often have congenital heart defects as well as other pathological conditions that shorten their life expectancy. Trisomy 18 is estimated to be present in 1/5,000 births.
• TRISOMY 13: It is caused by the presence of an extra copy of chromosome 13. Also known as Patau's Syndrome, it is associated with high abortion. Infants with trisomy 13 have numerous heart defects and other pathological conditions. Survival beyond one year of age is rare. Trisomy 13 is estimated to be present in 1/16,000 births.

Sex chromosomes aneuploidy

Turner syndrome, or Monosomy X, is the most frequent aneuploidy of the sex chromosomes. This syndrome is caused by the lack of a copy of the X chromosome. Only women, who have a shorter than average height, are affected. Some have heart or kidney defects, hearing problems, or learning difficulties.

Let's dig in to learn more details about this topic!

While most people have 46 chromosomes in their genetic makeup, including 2 sex chromosomes (46, XX in females and 46, XY in males), people with Turner syndrome usually only have 45 (45, X).

Turner syndrome is not passed on from parents, nor can it be passed on from mother to daughter, as women with Turner syndrome are very rarely fertile. At the moment, no environmental risk seems capable of causing this chromosomal anomaly and the mother's age does not play a fundamental role during the gamete formation phase. The mother's X chromosome is present in 70% of Turner syndrome patients, and the paternal X chromosome is present in the other 30%.

The main cause of the syndrome is the lack of sex chromosome disjunction during the meiosis phase (when two gametes - oocytes or sperm - with half the number of chromosomes are formed). Usually, the nondisjunction that leads to Turner syndrome is due to an error in the formation of the oocyte or, less frequently, of the sperm, resulting in the loss of a sex chromosome.

The chromosomal abnormality may, however, be present only in some cells of the body and not in all. In this case, it is defined as Turner syndrome with mosaicism of the chromosomes. In girls with mosaicism, symptoms are milder.

Aneuploidy Screening

An abnormality in the number of chromosomes in an embryo can be diagnosed prenatally with amniocentesis or CVS (Chorionic villus sampling, a form of prenatal diagnosis used to determine chromosomal or genetic disorders).

However, these invasive techniques have been largely substituted in recent years by screening that analyzes fetal DNA in the maternal circulation during the first trimester of pregnancy.

Ultrasound screening with nuchal translucency allows highly accurate predictions to determine the risk of autosomal aneuploidies (trisomies 21, 18, and 13) and of the sex chromosomes. If the test result indicates an increased risk, the result should be confirmed with amniocentesis or CVS.