What Causes Down Syndrome?

Chromosomes, Trisomy Types, Heredity, and Down Syndrome

girl with Down syndrome blowing on a dandelion
What causes Down syndrome and what is a trisomy?. Istockphoto.com/Stock Photo©DenKuvalev

Down syndrome is caused by an extra number 21 chromosome, but what does this really mean? What causes an extra chromosome? Can Down syndrome be inherited? To really understand what causes Down syndrome, you need to have a thorough understanding of what chromosomes are, and what they do. Understanding the genetics of Down syndrome is challenging, yet taking the time to digest this information can be reassuring to both parents-to-be who have concerns during pregnancy, and parents who have a child with Down syndrome who are asking themselves that difficult question: "Why?"

Packages of genetic information

The easiest way to think of chromosomes is as packages of genetic information. The human body is made up of all different types of cells and inside each of these cells, in the nucleus, are our genes. Genes are the units of inheritance that are passed from one generation to another. They are located in every cell of our bodies and they provide the instructions for every structure and function of our body. Humans have about 25,000 different genes. Rather than having all 25,000 bouncing around inside cells individually, our genes are located or packaged on chromosomes rather like pearls on a necklace.

Genes

Genes are made of DNA which is a molecule made up of four different chemicals called bases, which are usually referred to by their initials—A for adenine, T for thymine, G for guanine and C for cytosine. These 4 bases make up the "genetic code”—a sort of hereditary alphabet.

Genes are made up of small sections of DNA and these genes are located on chromosomes. If you think of bases as an alphabet, then genes can be thought of as sentences. Each sentence (or gene) provides a specific instruction for our bodies. One pair of genes might tell what color our eyes will be while another combination of genes might tell how small our little finger should be!

When scientists want to refer to all of our genes together, they call it a "genome."

Chromosomes

Chromosomes, as well as the genes located on them, come in pairs. Humans have a total of 46 chromosomes arranged into 23 pairs. The first 22 pairs of chromosomes are called "autosomes" and are numbered 1 to 22, from largest to smallest. The 23rd pair is called the "sex chromosomes" and consist of an X and a Y in males and two X chromosomes in females. Chromosomes can be seen under a microscope but the individual genes located on them cannot. The test which allows the chromosomes to be visualized (and counted) is a karyotype test,

Trisomy

Most people have 46 chromosomes or 23 pairs of chromosomes. People with Down syndrome have an extra number 21 chromosome for a total of 47 chromosomes. This condition is also called “Trisomy 21.” Trisomy comes from the Latin word "tri" which means three and "some" which means body and refers to chromosomes. People with trisomy 21 have three bodies 21, or three number 21 chromosomes.

Because chromosomes are the packages of genetic information and contain all of our genes or instructions, people with Down syndrome actually have three copies of all of the genes located on chromosome 21. It is estimated that there are 400 genes on chromosome 21. So basically, people with Down syndrome have 400 extra instructions. While having extra instructions sounds like it should be a good thing, it is actually like adding extra ingredients to a recipe. You will still get the same basic dish (a human body) but the form and function is different.

In addition to trisomy 21, there are other human trisomies. Down syndrome, or trisomy 21 is the most common autosomal trisomy, but babies with trisomy 13 (Patau syndrome) and trisomy 18 (Edward's syndrome) may also sometimes survive pregnancy. The life expectancy for children with these other trisomies is low relative to Down syndrome. Pregnancies with trisomy 15, 16, and 22 usually end in miscarriage. Trisomies in the other chromosomes are rarely seen and usually end in very early pregnancy miscarriage before an evaluation is possible.

Sex chromosome trisomies involving X and Y chromosomes are fairly common, for example, Klinefelter's syndrome (XXY) is estimated to affect 1 in 1000 males.

In contrast to trisomies, some chromosome abnormalities in babies are due to a decreased number of chromosomes, a 'monosomy." An example is Turner's syndrome in which one sex chromosome is missing, 45 X0 or monosomy X.

Causes of Trisomy

Trisomy for a specific chromosome is the result of a misdivision in the sperm or the egg prior to conception. Ordinarily the chromsomes line up and are separated evenly during division. With trisomies, both chromosomes go to one egg, so than when combined with the sperm (when the egg and sperm unite), there are three.

There is absolutely nothing that anyone can do to prevent a trisomy, and there is nothing that someone can do to cause a trisomy. It is an accidental occurrence that happens before conception (in complete trisomy) in either the egg or the sperm. We do not know what causes a trisomy to occur, though we know of some risk factors that increase the risk of this happening.

Types of Trisomy 21

There are three different types of trisomy 21:

Complete Trisomy 21 - Complete trisomy 21 is responsible for around 95 percent of Down syndrome. As noted above, when chromosomes line up to divide (to create eggs or sperm in a process called meiosis), instead of the two chromosome separating to go to different eggs, both chromosomes go to one egg and no chromosomes go to the other. This is called non-disjunction.

Translocation Trisomy 21 - Translocation trisomy 21 occurs in around four percent of babies with Down syndrome. In a translocation there are two copies of chromosome 21, but extra material from a third 21st chromosome is attached (translocated to) another chromosome. This type of Down syndrome may occur either before or after conception, and is the form that may sometimes be passed down (inherited.)

Mosaic Trisomy 21 - The least common for of Down syndrome, mosaic Down syndrome occurs when only some cells have an extra copy of chromosome 21. This form of trisomy occurs after conception, but it is not known why it occurs. Whereas people with complete trisomy 21 and translocation 21 are similar, mosaic trisomy 21 varies depending on the number of cells that have the extra chromosome.

Can Down Syndrome Be Inherited?

In general, Down syndrome is not 'inherited" but it may be passed from parents to children with translocation trisomy 21 (which accounts for around four percent of people with Down syndrome.) In roughly a third of people with translocation trisomy 21, the trisomy (two chromosome 21's plus extra chromosome 21 material attached to another chromosome) is inherited from a parent. The risk for someone with tranlocation trisomy 21 passing on the condition to a child is roughly 10 to 15 percent for women and three percent for men.

Since translocation trisomy 21 only accounts for around four percent of people with Down syndrome, less than one percent of cases would be considered hereditary.

If a child or adult with Down syndrome becomes pregnant, the risk of Down syndrome or other developmental disabilities in the baby is between 35 and 50 percent. Since many people with Down syndrome can lead very high functioning lives, and experience love and relationships just as those without Down syndrome, this is a risk that needs to be weighed against the benefits with the parents-to-be in a thoughtful manner. Roughly 50 percent of women with Down syndrome are able to become pregnant.

Risk Factors for Down Syndrome

Most parents who have a child with Down syndrome do not have any known risk factors. It's also important to note that, to date, there are no lifestyle or environmental risk factors for Down syndrome. In other words, with the exception of an increase with maternal age (and still most women who have children with Down syndrome are young) there is nothing that can help predict or prevent having a child with Down syndrome.

Maternal Age and Down Syndrome Risk

While trisomies can occur in people of any age, there is an association between a mother’s age and the chance to have a baby with a trisomy. An association is simply scientific term for a link. An association is not a cause. This is an important point, because people are often under the mistaken belief that maternal age causes Down syndrome. This is not true. We do not know what causes trisomies to occur. We simply know that as women get older, the risk for having a pregnancy with a trisomy increases.

While there is a link between maternal age and the occurrence of trisomies, most babies with Down syndrome are born to mothers under the age of 35. This is due to the fact that there are far more younger women having babies. In fact, 80 percent of babies born with Down syndrome are born to women younger than 35 and the average age of a mother of a baby with Down syndrome is 28 years. Overall, the likelihood of a woman under age 30 giving birth to a child with Down syndrome is less than 1:1000. The risk increases as a woman gets older, with an incidence of about 1:112 at 40 years of age. However, this is still less than one percent of women who become pregnant at age 40.

A chart comparing maternal age to Down syndrome risk is available, but it's important to caution women before looking at this chart. Make sure to keep in mind that the vast majority of women who become pregnant over the age of 35 have babies without Down syndrome.

Some women over the age of 35 (or with other risk factors) may choose to have an amniocentesis to screen for Down syndrome or other prenatal tests. The decision whether or not to have this these tests is very personal, and should be made with the assistance of genetic counseling. The American College of Obstetrics and Gynecology recommends that all women be offered prenatal testing for Down syndrome. Some women prefer to have this testing done both for reassurance and having the ability to plan ahead, while there are clearly reasons why women choose not to do prenatal testing as well.

Paternal Age and Down Syndrome Risk

It's estimated that the extra chromosome in Down syndrome comes from the mother the majority of the time and from the father (sperm) only four percent of the time. While advancing maternal age is correlated with Down syndrome risk, the same is not true for advancing paternal age simply due to the fact that eggs age, but sperm are continually made so that they are usually just a few weeks old. There are, however, genetic conditions other than Down syndrome which are linked with advanced paternal age, such as achondroplasia (dwarfism) and Marfan syndrome.

Research and The Future

With the talk about the Human Genome Project and gene therapy parents have asked a very good question: "Why can't gene therapy be used to repair the genetic abnormality in Down syndrome?" Unfortunately, our understanding of genetics isn't there yet. What gene therapy may be helpful with at least in the near future, is working with single gene abnormalities. Condition caused by more than one gene, let alone an entire chromosome would be difficult to treat with gene therapy. Researchers are therefore looking at what may be possible with epigenetic engineering—epigenetics is a field which looks at the expression (clinical manifestations) of genes rather than the genes themselves.

That said, the management of children born with Down syndrome has improved dramatically in the past few decades.

Bottom Line

The bottom line is that we know that there a link or association between a mother’s age and the risk to have a child with a trisomy such as Down’s syndrome, but no one knows the specific cause of trisomies.

Sources:

Dekker, A., De Deyn, P., and M. Rots. Epigenetics: The Neglected Key to Minimize Learning and Memory Deficits in Down Syndrome. Neuroscience and Biobehavioral Reviews. 2914. 45:72-84.

Mentis, A., Epigenomic Engineering for Down Synrome. Neuroscience and Biobehavioral Reviews. 2016. 71:323-327.

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