What is Aneuploidy?

In 2008, 64,343 children were born in New Zealand, 51% male and 49% female. All arose as a result of a successful conception, pregnancy and birth. However, pregnancy isn’t always straightforward and many conceptions do not result in live births or result in live births which bring with them challenges for both parents and child, associated with potential or actual health issues.

About 15% of all confirmed pregnancies result in miscarriage. Additionally, many miscarriages occur before a woman has missed her period and therefore may not know that she is pregnant. Chromosome abnormalities within the embryo are the most common cause of miscarriage in early pregnancy. 

All parents hope that their children will have a healthy life. Scientists know that a good start to life is a pre‐requisite to a long and healthy life. There are many factors that determine whether a child has a healthy start to life. Some of these, such as the environment in the womb can be determined by what the mother eats and whether she uses drugs during the pregnancy. Others, such as the genes that are inherited by the embryo at conception cannot be controlled. Worldwide, 6% of infants are born with serious birth defects. Some of these conditions can be treated and controlled, some lead to an increased susceptibility to disease over a lifetime, while others cause permanent disabilities, significant pain and suffering and may lead to premature death.

An example of an inherited genetic condition is Haemophilia, a disease in which the blood will not clot, leading to significant suffering and potentially uncontrolled bleeding that may result in early death. Haemophilia is an example of a gene mutation, which is a change in the DNA sequence that makes up a gene. The mutation that causes this disease is found on the X‐chromosome and has been passed down the lineage of the Royal families of Europe for many generations. Sickle-cell anaemia is another example of a devastating genetic disorder that is caused by a change to a single gene. Other conditions may be caused by chromosome abnormality or mutation, where a whole chromosome or segment of a chromosome may be missing, added or altered. 

Many people who know that they carry the genes for genetic disorders are troubled by the thought of giving birth to a child that will be unwell or suffer during their lifetime. Some people in this situation make the decision not to have children to avoid this suffering. Advances in biotechnologies over the past 20 years have led to the potential for couples in this situation to use early warning systems to give them an indication of what lies ahead and make a very early decision about whether to proceed with the pregnancy or not. 

Aneuploidy is caused by the failure of chromosomes or chromatids to separate during cell division. This is called non-disjunction and can happen either during meiosis or mitosis.

Non‐disjunction during meiosis results in gametes that are either n‐1 or n+1. Fertilisation of these gametes by a normal gamete will result in an aneuploid embryo, either monosomy (2n‐1) or trisomy (2n+1).

Down Syndrome (Trisomy 21) 

Down Syndrome is caused by the presence of an extra copy of chromosome 21 (Fig 1c) and is the most common form of aneuploidy that is seen in humans. Many pregnancies with Down Syndrome miscarry, so while in New Zealand Down Syndrome will occur in 1 in 400 pregnancies it is only seen in 1 in 700 live births. The occurrence of Down Syndrome increases with increasing maternal age, rising from 1 in 1000 for 20-29 year old mothers to 1 in 90 for 40 years old mothers. The extra copy of chromosome 21 causes a range of physical, intellectual and physiological phenotypic characteristics in people with Down Syndrome which will have a life‐long effect. 

There is no cure for Down Syndrome and there are no recognised environmental factors that lead to Down Syndrome. Some of the more common physical features that are shared by people with Down Syndrome include flattened facial features, protruding tongue, small head, upwardly slanting eyes and unusually shaped ears. They also tend to have poor muscle tone, relatively short fingers and hands, are short in stature and grow slowly. Heart and gastro‐intestinal problems are also more common in children with Down Syndrome. Down Syndrome children usually have a moderate degree of intellectual impairment. While some can participate to varying degrees in school, work and social life, others have severe intellectual disabilities. Effective early education interventions will assist Down Syndrome children to maximise their potential.

The extra copy of chromosome 21 found in Down Syndrome can arise in three different ways:

Non‐disjunction during meiosis leading to Trisomy 21 (90— 95% of cases) 

• The extra copy of chromosome 21 arises as a result of non‐ disjunction during meiosis and results in a gamete with an extra copy of chromosome 21. This is fertilised by a normal gamete (Fig 2)

Mosaic Trisomy 21 pattern (<3% of cases) 

• The extra copy of chromosome 21 arises as a result of non‐ disjunction during mitosis in the early embryo. This results in some cells that are normal and some that have the extra copy of chromosome 21.  The earlier this occurs in embryonic development, the more cells are affected and the more significant the effect (Fig 4)

Translocation (very uncommon) 

• In this situation there are two normal copies of chromosome 21 plus an additional copy of all or part of chromosome 21 attached to another chromosome (typically chromosome 14) (Fig 5)

Fig. 7 shows that the incidence of Down Syndrome increases significantly in older women. A woman’s eggs are formed while she is in the womb. Even before she is born, the number of immature eggs in her ovaries is decreasing. She is born with all the eggs that she will ever have, as many as 1‐2 million, in a state of suspended development. By the time she reaches puberty only 400,000 will remain. By the time she reaches her late 30s the number will be down to as few as 20,000 and by the time she reaches her mid 40s there will only be a few hundred left.

As well as the number of eggs reducing dramatically over this period, the quality of the eggs will also reduce. This is why as women get older they are less likely to become pregnant each month and the incidence of miscarriage and chromosomal abnormality increases. The direct relationship between age and the incidence of aneuploidy suggests that the mechanism of separation (or disjoining) of the chromosomes or chromatids during meiosis is becoming less effective with increased age of the eggs. 

What About the Father? The Paternal Age Effect 

In contrast to women who have a limited supply of eggs, men are able to produce sperm throughout their lives. However, is sperm quality retained into old age? While it is known that most cases of Down Syndrome are a result of non-disjunction in the female gamete, 5‐10% of Down Syndrome is caused by non-disjunction in the male gamete (the sperm), however there is no conclusive evidence that this is more common in older fathers. Aneuploidy affecting the sex chromosomes is more often caused by a faulty sperm and evidence suggests that there is around a two‐fold increase in this for men over the age of 50 (Sloter, Nath, Eskenazi, & Wyrobek, 2004). 

It is also clear that environmental factors such as smoking (tobacco or marijuana), alcohol and excess weight in the father all appear to be detrimental and appear to increase the risk of long term health effects for their children. Smoking more than 10 cigarettes a day in men increases the risk of childhood cancer in their children fourfold.