Trisomy: What Is, Causes, and The Most Common Trisiomies

What Is Trisomy?

A human typically possesses 23 pairs of chromosomes within each body cell, except for the reproductive cells. Consequently, each cell carries genetic information, consisting of 23 chromosomes inherited from the mother and another 23 homologous chromosomes from the father.

The complete set of human chromosomes (the karyotype) comprises 22 pairs of autosomal chromosomes (autosomes) and a couple of sex chromosomes (allosomes). However, egg and sperm cells have only half of the entire chromosome set, equivalent to one chromosome from each homologous pair, totaling 23 chromosomes.

This reduction in genetic material is crucial to ensure that upon fertilization, the egg and sperm cells unite, resulting in the new organism having the correct amount of DNA packed in 23 pairs of chromosomes or 46 chromosomes.

Trisomy is a type of numerical chromosomal abnormality, also known as aneuploidy, which occurs when all or some body cells contain an additional third chromosome in a given homologous pair. The prefix “tri-” indicates the presence of an extra third chromosome instead of the correct pair of chromosomes. Trisomy can affect both autosomal and sex chromosomes.

The normal karyotype of a man is written as 46, XY, and the standard karyotype of a woman is written as 46, XX. Additional chromosomes in the karyotype are given after a plus sign, e.g., 46, XX,+18, which means a woman with trisomy 18.

Causes

In such a situation, the causes of trisomy are related to errors in chromosome separation during the formation of egg cells and sperm (during gametogenesis) or during cell divisions that occur after fertilization (during embryogenesis):

Nondisjunction (not separating) of homologous chromosomes in the first meiotic division of gametogenesis
Nondisjunction of homologous chromosomes in the second meiotic division of gametogenesis
Nondisjunction of homologous chromosomes during embryogenesis during mitotic division

Link to Genetic Disorders

Chromosomal abnormalities, including trisomies, are linked to genetic disorders. Chromosomes, which are composed of deoxyribonucleic acid (DNA) and proteins, carry genetic information that regulates human body development and function. DNA is a genetic material that is composed of nucleotides arranged in sequences that form genes encoding specific traits in humans. Each gene is assigned a permanent locus on a chromosome. Both excess and deficiency of genes are detrimental to human health.

Trisomy, a condition characterized by an excess of genetic material, can be fatal and its severity depends on the affected genes. Most chromosomal disorders of this kind are lethal during reproductive cell formation and can lead to miscarriages or stillbirths. Trisomies account for around 0.3% of all live births.

Balanced Translocation

Trisomy can also result from one parent having a balanced translocation. Balanced translocation means that part of a chromosome has moved to another place in the genome (usually, a chromosome fragment has joined another chromosome). Even though we are dealing with some structural disorders kind, genetic material has neither been lost nor added, and it usually does not affect the health of the person with such a translocation.

Moreover, we often do not know we are carriers of a balanced translocation. However, such a translocation may affect the quality of the we will produce reproductive cells. Depending on where the chromosome fragment has moved, it is possible to produce gametes with the correct set of chromosomes, with an excess or a deficiency of genetic material. The diagram below shows one possible situation.

trisomy-what-is-causes-the-most-common-trisiomies-120043

Risk factors

The most important factors increasing the risk of trisomy in a child are:

Age of the woman planning pregnancy (the risk of trisomy increases with the mother’s age)
Balanced translocation in one of the parents
Previous pregnancy with trisomy

The Most Common Trisomies

There are several forms of trisomy:

Full trisomy – occurs when an additional third chromosome is in every body cell.
Translocation trisomy – the characteristic feature of this type of trisomy is the presence of part of an extra chromosome, not the entire extra chromosome. This trisomy results from a translocation – an additional part of the chromosome has moved and attached to another chromosome.
Mosaic trisomy – an additional chromosome is present only in some cells of the human body. In the case of mosaic trisomy, the symptoms characteristic of a given genetic disease are usually less severe.

Let’s focus on one of the most common trisomy types.

What is Down Syndrome?

Down syndrome means the combination or co-occurrence of characteristic morphological and clinical features in a specific combination in people with a similarly altered genetic information record.

Down syndrome is caused by the duplication of all or a critical part of chromosome 21. Such rearrangement of the genetic material most often occurs due to an error during the separation of chromosomes during meiosis.

Unbalanced translocations involving chromosome 21 may also lead to Down syndrome. It can only occur in the fetus due to the accidental connection of chromosome 21 with another chromosome.

Unbalanced translocations may also result from inheriting a linked chromosome 21 from one of the parents, who is a carrier of a balanced translocation (exchange of chromosome fragments without changing the amount of genetic material).

What is the Risk of Having a Child with Down Syndrome?

Inheriting an altered chromosome is a random event because the reproductive cells of a translocation carrier may contain both normal and erroneous chromosomes. The most difficult from the point of view of genetic counseling is the case of the presence of a translocation in one of the parents between two chromosomes 21, 21 -t (21; 21).

In such a case, the probability of giving birth to a child with Down syndrome, regardless of whether the mother or father is the carrier of such a translocation, is close to 100%, which means that every child in this family will be affected by Down syndrome.

The smallest or shortest segment of chromosome 21, the duplication of which manifests itself as Down syndrome, is called the critical region. Chromosome 21 contains relatively few genes compared to other chromosomes. However, there are approximately 250 genes on chromosome 21.

The genes influencing the occurrence of Down Syndrome are:

The gene encoding superoxide dismutase SOD1, which, if present in excess, causes premature aging of the body and immune disorders.
The gene for collagen VI, overexpression may cause heart and large blood vessel defects, reduced muscle tone, and joint laxity.
The oncogenic ETS2 gene, the product of which is responsible for the development of skeletal system pathologies (low body height, disturbed proportions between the trunk and limbs, abnormal skull structure).
CAF1A influences DNA synthesis and chromatin structure.
Cystathionine ß-synthetase CBS influencing metabolism and DNA repair.
The gene whose product is responsible for intellectual disability in Down syndrome is DYRK1A, which encodes a kinase that causes memory and learning disorders.

Characteristic Features

People with Down syndrome have several characteristic features. Some manifest themselves in appearance, and some are not visible and can only be observed during specialist tests.

The main characteristic features include:

Reduced muscle tone
Oblique positioning of the palpebral fissures
Low body height
Small head, flattened in the occipital part, shortened in the anterior-posterior dimension (shortcephaly), round and flat face, epicanthic wrinkle, stellate, regularly arranged light spots on the iris
The nose is small, short, and flat, with a wide base, and the bridge of the nose is sunken
Smooth, sparse, and straight hair
Ears small, deformed, set low
Thick lips, cracked, lower lip turned out, often open, large tongue sticking out
Gothic palate
Teeth are not properly spaced
The neck is short, with a skin fold
Hands and feet are wide and short, palmar and sandal crease, flat feet or flat-valgus foot
Dry, rough, and marbled skin

trisomy-what-is-causes-the-most-common-trisiomies-478391

Patau Syndrome

Patau syndrome is a group of severe congenital defects caused by the presence of an additional chromosome 13 or part of it. It is a rare lethal aberration, i.e., it does not allow the baby to survive beyond the neonatal period. The incidence of Patau Syndrome in the general population is low, approximately 1.2 per 10,000 live births. In a significant percentage of pregnancies with trisomy 13, spontaneous miscarriage occurs during the embryonic or fetal period.

Patau syndrome, which is a simple trisomy involving the presence of an additional copy of chromosome 13, is not a hereditary disorder (it is not revealed as a result of inheriting an additional chromosome). It is usually the result of the formation of an abnormal gamete, i.e., a reproductive cell (sperm in a man, egg in a woman).

Simple trisomy 13 is, therefore, most often a random event, the risk of which increases with the mother’s age. The additional chromosome is usually of maternal origin and appears in the first meiotic (reduction) division.

Patau syndrome may result from a balanced translocation in one of the parents concerning chromosome 13. Most often, it involves the displacement of the long arm of chromosome 13 to chromosome 14 or 15. This type of genetic material disorder does not produce a phenotypic effect, i.e., it is not revealed in the form of observable features of a given individual (body structure, behavior, presence of congenital defects, occurrence of specific diseases).

The carrier of the translocation is usually a healthy person. However, a balanced defect in the genetic material may lead to the formation of abnormal reproductive cells.

The Risk of Having A Child With Patau Syndrome

Data from the literature in this area vary significantly, which results from different methods of calculating the individual risk for individual patients with an abnormal karyotype.

Symptoms

Children with Patau syndrome present a particular morphological phenotype. Immediately after birth, the following characteristic features can be observed:

Low newborn body weight
Decreased muscle tension
Convulsions
Breathing disorders
Congenital developmental defects, including heart defects and kidney defects (cystic kidney disease and hydronephrosis)
Anatomical defects of the brain, e.g., holoprosencephaly
Eye defects, including microphthalmia and absence of iris
Genital defects

Treatment

Patau syndrome is an incurable disease and requires only symptomatic (palliative) treatment. The most noticeable symptoms of Patau syndrome include the characteristic appearance of newborns, including a small head with closely spaced eyes, an undeveloped jaw, or incorrect hand structure.

Most newborns with Patau syndrome cannot be fed naturally. Due to impaired sucking and swallowing reflexes, feeding requires the use of a probe inserted into the stomach. Eating disorders are accompanied by gastroesophageal reflux. Newborns gain weight poorly, and their psychomotor development does not progress.

Edwards Syndrome

Edwards syndrome, i.e., trisomy of chromosome 18, is a rare chromosome aberration. There is the presence of an additional chromosome pair 18.

In a significant percentage of pregnancies with trisomy 18, spontaneous miscarriage occurs in the embryonic or fetal period. Some fetuses survive the prenatal period, but still, many newborns with Edwards syndrome die within the first weeks after birth.

People diagnosed with Edwards syndrome manifest several features regarding both appearance and abnormalities in the structure of internal systems and organs.

Symptoms

Characteristic symptoms of Edwards syndrome include:

Growth disorders (fetal and postnatal period)
Low birth weight
Narrow chest
Short and wide bridge
Microcephaly
Narrow skull
Small lips
Underdevelopment of the lower jaw
Protruding occiput
Hypertelorism (larger than expected distance between pupils) and narrow eyelid fissures
Deformed low-set auricles
Deformation of limbs (e.g., existence of additional fingers, nail hypoplasia, hands clenched into a fist, and fingers overlapping)

Sources

Trisomy. NIH.
https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/trisomy
Genetics, Chromosome Abnormalities. NIH.
https://www.ncbi.nlm.nih.gov/books/NBK557691/
Genetics, Chromosomes. NIH.
https://www.ncbi.nlm.nih.gov/books/NBK557784/
Mechanical Mechanisms of Chromosome Segregation. NIH.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926803/
Detection of a balanced translocation carrier through trophectoderm biopsy analysis: a case report. NIH.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582470/
Down Syndrome. NIH.
https://www.ncbi.nlm.nih.gov/books/NBK526016/
What are the symptoms of Down syndrome?. NIH.
https://www.nichd.nih.gov/health/topics/down/conditioninfo/symptoms
Patau Syndrome. NIH.
https://www.ncbi.nlm.nih.gov/books/NBK538347/
Patau’s syndrome. NHS.
https://www.nhs.uk/conditions/pataus-syndrome/
Edwards Syndrome. NIH.
https://www.ncbi.nlm.nih.gov/books/NBK570597/
The trisomy 18 syndrome. NIH.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520824/