Trisomy is a genetic condition where a chromosome has 3 copies instead of the normal two. March, the third month of the year, is Trisomy Awareness month. While some trisomy conditions, like Trisomy 21 (Down syndrome), Trisomy 18 (Edward’s syndrome) and Trisomy 13 (Patau syndrome) are well known, there are more trisomy syndromes that receive little recognition yet play a critical part in pregnancy, survival, and an individual’s health.

To understand the significance of trisomies, one must first acknowledge the role and mechanisms of chromosomes. Chromosomes carry ‘the recipe’ for characteristics that are passed from parents to their offspring, like eye and hair color, within genes. Genes make up all the genetic information of a person, and also control protein functions that are essential for our bodies to work properly. Accordingly, chromosomes define the features and the health of an individual.

Each species has a set number of chromosomes which carry a number of genes that code for certain characteristics and proteins. Ranging from 2 chromosomes in a species of roundworm to 1260 in a type of fern plant, potatoes have 48, horses have 64, and humans normally have 46 chromosomes arranged in 23 pairs. From these 23 pairs, 22 pairs are called ‘autosomal’. These are chromosomes 1 to 22 that control general genes and functions of our body. Chromosome pair 23 contains the sex chromosomes. These determine the gender of an individual, with females carrying two X chromosomes (XX), and males carrying an X and a Y (XY).  From an evolutionary standpoint, the chromosome number doesn’t matter – it’s the number of genes on the chromosomes that is significant. These can be spread out on the chromosomes or, as in humans, be closely packed together.

Half of each chromosome pair is inherited from the father, and the other half is inherited from the mother. During cell division, when chromosomes divide and make new ‘daughter’ cells that carry the same genetic information, chromosome numbers must divide equally.

Problems arise when there is an abnormal number of chromosomes, leading to an excess or a depletion of genes that disrupt the genetic balance. In most cases concerning the autosomal chromosomes, these errors occur due to increased maternal age. While sperm is continually produced in a male, with the average sperm production taking about 65 days, all the oocytes – that will mature into eggs – of a female are already produced since she was a fetus. Therefore, a female egg is chronologically the same age as the woman. The older the eggs are, the more likely the repair mechanisms that are in place to prevent mistakes in cell division will fail.

Trisomies occur during errors in cell division. During reproduction, the egg and the sperm, carrying 23 chromosomes each, fuse together and create a zygote of 46 chromosomes. This single cell will repeatedly multiply and divide its genetic material, cell by cell, to form the fetus, the placenta and the umbilical cord. During fertilization and early development cell divisions, mistakes can occur and cells can end up with a higher or lower number of chromosomes. For example, a cell can end up with 3 copies of chromosome 18. If this copy is not corrected through the organism’s repair mechanisms, it can end up in the developing embryo. The error will be repeated in all subsequent daughter cells as the faulty cell continues to divide, and the baby will have a high risk of developing Trisomy 18. The severity of the condition depends on whether the trisomy affects the whole chromosome or is partial (duplication), how early in the development stage the error occurred – which determines the percentage of abnormal to normal cells (mosaicism) – and on the affected chromosome.

Sex chromosome trisomies, concerning the 23rd pair of chromosomes, are hypothesized to be due to paternal errors in failing to properly separate the X and Y chromosomes1. Such trisomies, like Triple X (XXX), or Klinefelter syndrome (XXY), can affect life quality, but not survival. Symptoms include delayed development, infertility and mild to moderate distinct appearance. Difficulty in postnatal diagnosis is common due to symptoms variability and usually happens after adulthood, so Non Invasive Prenatal Testing (NIPT) is useful for early clinical management. Generally, they are less severe than autosomal trisomies. This is due to the ‘X-inactivation’ mechanism, that always ‘shuts off’ one of the two X chromosomes so females don’t have twice the number of genes as males – which could be toxic. Interestingly, the same X doesn’t get silenced in all cells – the process is random – explaining the symptom variability in sex chromosomes disorders. This is why tricolor, calico and tortoiseshell cats are primarily females; their fur color gene that carries 2 color variations is X-linked.

Trisomies 21, 18 and 13 are the most well-known autosomal aneuploidies, as they are the only trisomies resulting in a liveborn infant. Children affected by these trisomies have a range of birth defects like heart abnormalities, delayed development and intellectual disabilities. Trisomy 21 has the milder clinical presentation of the three. A very high percentage of children with Down syndrome have serious heart defects; however, most individuals cope well when having a close support system. Fetal mortality is high in Trisomies 18 and 13, and less than 15% of babies survive past their first year of life2,3. These trisomies affect survival and quality of life, however there are other trisomies that also affect pregnancy viability.

50-70% of pregnancy losses are due to chromosomal abnormalities, with autosomal trisomies accounting for 60% of these losses4. Trisomies 16 and 22 are the commonest causes of spontaneous miscarriage during pregnancy, with most losses happening in the first trimester. Unfortunately, there is no prevention or treatment. In the exceptionally rare event that babies are carried to term, they are unable to survive for more than a few days due to the severity of birth defects that include heart and kidney abnormalities, and muscle weakness. Trisomies 8 and 9 are also severe, resulting in newborn death within the first months or days of life. These conditions are extremely rare, and are characterized by heart defects, cleft palates, joint malformation and kidney problems.

Trisomy Awareness Month is celebrated to spread knowledge, support and understanding about children affected with trisomies and their families. It’s a time to raise awareness on the challenges faced, remember all the lost pregnancies and the babies that have been sadly gone. Unfortunately, the exact mechanisms leading to trisomies are unknown and their prevention is impossible. NIPT for the detection of trisomies 21, 18, 13, X and Y early in the pregnancy are available, which make it possible for prospective parents to receive all the necessary information about the health of their baby as soon as possible. This enables them to take informed decisions about crucial medical management, their pregnancy and the future of their family.

VERACITY and VERAgene both test for autosomal and sex chromosome trisomies from the 10th week of pregnancy. For more information, please visit www.nipd.com

References:

  • Bacino et al. (2011). ‘Chapter 76: Cytogenetics’. In Kliegman RM et al. Nelson Textbook of Pediatrics, 19th Edition, Philadelphia: Saunders. Pp 394-413.
  • Cereda A. and Carey J.C. (2012). ‘The trisomy 18 syndrome’. Orphanet Journal of Rare Diseases, 7:81.
  • Peroos S. et al. (2012). ‘Longevity and Patau syndrome: what determines survival?’ Case Reports, 2012:bcr0620114381
  • Silver R.M. and Branch D. (2007) ‘Sporadic and Recurrent Pregnancy Loss’. Clinical Obstetrics: The fetus & mother, 3rd edition, Blackwell Publishing, Boston, pp 143-160.