An Explanation for Us All

When the medical world first learned about Prader-Willi syndrome in 1956, doctors had no idea what caused people to have this collection of features and problems that we now know as PWS. In 1981, Dr. David Ledbetter and his colleagues reported a first breakthrough discovery: Many people with PWS that they studied had the same segment of genes missing from one of their chromosomes. They had discovered the deletion on chromosome 15 that accounts for about 70 percent of the cases of PWS.

Since then, researchers have made a series of other important discoveries about the genes involved in Prader-Willi syndrome. Thanks to their perseverance, we now know much more about the several genetic forms of this complex disorder, and we have genetic tests that can confirm nearly every case.

Chromosomes and Genes: The Basics

To understand the genetics of PWS, it helps to have a basic understanding of chromosomes and genes. Chromosomes are tiny structures that are present in nearly every cell of our bodies. They are the packages of genes we inherit from our parents. Genes contain all the detailed instructions our bodies need to grow, develop, and function properly—our DNA. Specific genes direct our cells to produce proteins, enzymes, and other essential substances. Each of our many genes is located on a specific chromosome. Most of our body’s cells contain 46 chromosomes—23 inherited from our mother and 23 from our father. (Egg and sperm cells normally contain just 23 chromosomes, because those are the cells that join in conception and provide the baby the right number of chromosomes.) Twenty-two of the chromosome pairs are labeled with a number based on their size (chromosome 1 is the largest pair, and chromosome 22 is nearly the smallest), and the two chromosomes in each numbered pair contain the same genes (one set from mother and one from father). The changes that cause Prader-Willi syndrome occur on the pair known as chromosome 15. The 23rd chromosome pair is designated as the sex chromosome pair This pair determines the baby’s sex: XX for a girl, XY for a boy.

Changes or errors in genes and chromosomes are common in the formation of egg and sperm cells. Some of these genetic changes will have no effect when a baby is conceived; some will cause a miscarriage; and some, like those in Prader-Willi syndrome, will cause significant differences in how the baby develops and functions. While many genetic disorders are caused by a change in a single gene and can be passed down from parent to child, PWS is more complicated.

Some of the important genetic characteristics of PWS identified through research are:

  • More than one gene is involved in PWS, and these genes are near each other in a small area of what is called the “long arm” of chromosome 15—in a region labeled 15q11-q13. Scientists still don’t know exactly how many genes and which specific ones are involved.
  • The critical genes must come from the baby’s father in order to function properly; the mother’s genes in this area are “turned off” through a rare phenomenon called “genomic imprinting.”
  • There are at least three different chromosome errors that can keep these key genes from working normally, and all result in the child having Prader-Willi syndrome.
  • The two most common errors that cause PWS can occur in any conception—in other words, PWS is not usually an inherited condition; it just happens. In very rare cases, however, parents may have a 50-percent chance of having another child with PWS.

The Role of Genomic Imprinting

During the early 1980s, scientists puzzled over why some people who seemed to have PWS did not have the chromosome 15 deletion, and why some people with the chromosome 15 deletion seemed to have a different condition from PWS. Dr. Merlin Butler and colleagues began unraveling the puzzle when they reported in 1983 that the chromosome 15 deletion in PWS was on the father’s chromosome.

The next breakthrough came in 1989, when Dr. Robert Nicholls and fellow researchers announced their discovery that PWS is an example of genetic or genomic imprinting, a process well known in plant genetics but not previously identified in humans. This means that some of our genes have to come from a particular parent to work normally. These rare genes are said to be “imprinted,” or have the ability to be turned off or on, depending on which parent contributed the gene. In what scientists call the “Prader-Willi region” of chromosome 15 (the area where the deletion occurs), there are genes that must come from the baby’s father that are active, or “expressed,” in order to work. These genes are not active or expressed on the chromosome 15 inherited from the mother because the mother’s imprint turns them off. In Prader-Willi syndrome, these critical genes are either missing (deleted) from the father’s chromosome 15, functioning improperly because of an imprinting defect, or the entire chromosome 15 from the father is missing and both chromosome 15s come from the mother. (See The Three Genetic Forms of PWS for more detail on each of these errors.)

When a deletion of chromosome 15q11-q13 region is found on the mother’s chromosome 15, the result is an entirely different syndrome called Angelman syndrome (AS). That is because there is also one gene in the Prader-Willi region that is imprinted, or turned off, on the father’s chromosome 15; people who lack this gene from their mother have AS rather than PWS. This discovery explained the mysterious cases of people who had a chromosome 15 deletion but did not have the characteristics of PWS—their deletion was on the chromosome 15 that came from the mother. Because the genetic errors happen in the same section of chromosome 15, PWS and AS are sometimes called “sister” syndromes even though the disorders have few features in common.

The Three Genetic Forms of PWS

Although every case of Prader-Willi syndrome is due to the baby failing to receive active genes from a specific section of the father’s chromosome 15, there are three different ways that this can happen:

Paternal deletion — about 70% of all cases of PWS

 In the most common form of PWS, part of the chromosome 15 inherited from the child’s father—the part containing the PWS critical genes—is missing. In some cases, the section that has disappeared (called a “deletion” or sometimes a “microdeletion”) is large enough to be identified with high resolution chromosome studies done with a microscope; in other cases, it is too small but it can be detected with another chromosome test called FISH (see Tests Used To Diagnose Prader-Willi Syndrome). Typical or common deletions are now classified as Class/Type 1 or Class/Type 2, based on the size of the deletion. Usually a deletion happens for no known reason, and it is not likely to happen again in another pregnancy (less than 1% chance of recurrence). There is nothing the father did (or did not do) to cause it and no way to prevent it. Note: In rare cases of atypical deletions, imprinting defects (see below), or when a chromosome change such as a “translocation” caused the PWS genes to not function normally , the family could have another child with the same condition. (In a translocation, part of one chromosome is broken off and attached to a different chromosome.) It is especially important for these families to have further testing and genetic counseling.

Maternal uniparental disomy (UPD) — about 25% of cases

In this less common form of PWS, the baby inherits both copies of chromosome 15 from one parent—the mother. (Maternal means mother; uniparental means one parent; and disomy means two chromosome bodies). In these cases, the developing baby usually starts out with three copies of chromosome 15 (a condition called trisomy 15) because there was an extra chromosome 15 in the mother’s egg. Later, one of the three is lost—the chromosome 15 that came from the father’s sperm. The result has the same effect as a deletion. The child does not have active genes on chromosome 15 that must come from the father in order to be expressed (to function). Even though there are two complete copies of the mother’s chromosome 15, the key genes in the PWS region are imprinted, or turned off, in the mother’s copies. Because the error in this form of PWS starts with an extra chromosome in the mother’s egg, and older eggs are more likely to have errors of this type, older mothers are more likely than younger mothers to have a baby with this form of PWS. Even so, it is not likely to happen (and hasn’t yet) to a second child in the same family. When a baby inherits two identical chromosome 15s from the mother (isodisomy, or two copies of the same one rather than one of each of the mother’s own chromosomes), there is a chance of having additional genetic problems or conditions.

Imprinting defect — less than 5% of cases

In very rare cases, the PWS genes on the father’s chromosome are present but do not work because the imprinting process is faulty. The activity of the genes is controlled by a tiny imprinting center on chromosome 15 in the same area as the PWS critical genes. Normally, when genes are passed down to a child, the prior imprints are cleared away, and new imprints are made according to the sex of the parent. When there is a microdeletion or other defect in the imprinting control center, gene function on the father’s chromosome 15 may not be set to work normally. An imprinting defect can appear suddenly, or it can be present in the father’s chromosome that he received from his mother. If he received the defect from his mother, the father would not have PWS himself (because it’s on his maternal chromosome 15), but he could pass it on to his child (it would be the child’s paternal chromosome 15). There is a 50-50 chance that any child he has will receive the chromosome with the defect instead of the one that’s working correctly. Likewise, the father’s siblings could carry and pass on the mutation to their children. Further testing and genetic counseling are especially important for families who have a child with an imprinting defect.

Genetic Tests for PWS

Because the genetics of PWS is so complicated, it usually takes more than one test to be certain whether someone has PWS and what form of it they have. The major tests that are used in the diagnosis of PWS are shown in the table below. Which genetic tests are used, and in what order, will depend on a number of considerations for each individual case (see Testing Considerations). Genetic testing usually requires a blood sample from the child and possibly from the parents as well.

Families should consider genetic testing for PWS if they have:

  • a baby with low muscle tone (hypotonia), poor sucking ability, and — if a boy — undescended testicles;
  • a child or adult who has a number of the characteristics of Prader-Willi syndrome as listed in the Diagnostic Criteria for PWS; or
  • an undiagnosed child who was tested for PWS using older tests than those available today.