Prevalence,Genetics and Inheritance

//Prevalence,Genetics and Inheritance
Prevalence,Genetics and Inheritance 2017-06-29T16:40:20+00:00
Fragile X Prevalence

Fragile X Prevalence

How Common is Fragile X Syndrome?


There have been a number of studies aimed at determining the prevalence of FXS in males and females. Studies have been undertaken both in the “special needs” population and the general population. The agreed upon prevalence of FXS in males is approximately 1 in 3,600 to 4,000 and in females is approximately 1 in 4,000 to 6,000.

The reason it is lower in females is that, while all males with an FMR1 full mutation will have Fragile X syndrome, some females with an FMR1 full mutation will not have behavioral, cognitive or physical features of FXS.

How Many Individuals are Carriers of the FMR1 Premutation?

According to a 2012 study by the CDC, the frequency of Fragile X premutation is as follows:

  • 1 in 151 females, or about 1 million women in the United States.
  • 1 in 468 males, or about 320,000 men in the United States.

These statistics are important because both men and women are at risk for having symptoms linked to Fragile X-associated Disorders.

  • Women with a premutation reported their last menstrual cycle at an earlier age than women without a premutation (48 vs. 51 years).
  • Men and women with a premutation were more than four times as likely to report dizziness or fainting as people without a premutation (18% vs. 4%). Men and women with a premutation were more than twice as likely to report numbness as people without a premutation (29% vs. 13%).

This study of 6,747 older adults in Wisconsin found 30 people with a change in the FMR1 gene. Based on this relatively small number of people, the results should be interpreted with caution. These findings may not reflect all people in the United States with an FMR1 premutation For example a large Israeli study found approximately 1/130 women were FMR1 carriers.

Prevalence of FXTAS

Current estimates suggest that about 30-40% of male FMR1 premutation carriers over 50 years of age, within families already known to have someone with Fragile X, will ultimately exhibit some features of FXTAS.

This figure may be as low as 10-20% in the general population, since the majority of carriers have a premutation in the lower range of CGG repeats, where the occurrence of FXTAS appears to be reduced.

Though there are specific diagnostic criteria for FXTAS, some men may only exhibit some of the symptoms, and may not develop all of the cardinal features of the condition.

For men who are premutation carriers, the chance of developing core symptoms of FXTAS (tremor, problems with walking/balance) increases with age.

  • From age 50-59 the chance is about 17%.
  • From age 60-69 about 38%.
  • From age 70-79 about 47%.
  • Over 80 years old, about 75% will develop symptoms of FXTAS.

Studies of females have found that about 8-16% of premutation carriers, within families already known to have someone with a Fragile X condition, develop some FXTAS symptoms. The symptoms in females tend to be milder.

FXTAS may be one of the most common adult onset, single-gene neurological diseases; similar in prevalence to other neurodegenerative diseases such as ALS (Lou Gehrig’s disease); however more studies within the general population will be necessary before the true incidence is known.

Prevalence of FXPOI

  • Approximately 20-25% of women with an FMR1 premutation will develop FXPOI. FXPOI covers a range of ovarian difficulties including early menopause, irregular menstrual cycles, infertility, sub fertility and premature ovarian failure (cessation of menstrual periods prior to age 40)

How Common are Intermediate (Grey Area) Alleles?

Approximately 1 in 50 (2%) of individuals have an intermediate allele. There appear to be no clinical associations with intermediate alleles. Most intermediate alleles are stable and do not change over generations. In a small number of families intermediate alleles show some slight instability and can lead to a premutation in future generations. Individuals with an intermediate allele are not at risk for any for the FXDs or to have children with Fragile X syndrome.

Based on the best available evidence:

  • Approximately 1 million Americans carry the Fragile X mutation, including approximately 100,000 with Fragile X syndrome, and are at risk for developing a Fragile X-associated Disorder.
  • Approximately 1 in 3,600 to 4,000 males in the world are born with the full mutation for Fragile X.
    Note: The vast majority of males with the full mutation will have Fragile X syndrome.
  • Approximately 1 in 4,000 to 6,000 females in the world are born with the full mutation for Fragile X.
    Note: Approximately 50% of females with the full mutation will have some features of Fragile X syndrome.
  • Approximately 1 in 468 men in the world are carriers of the Fragile X premutation.
  • Approximately 1 in 151 women in the world are carriers of the Fragile X premutation.
male chromosomes
male chromosomes
Female Chromosomes
Fragile X Chromosome

Genetics and Inheritance

What Are Chromosomes?

Our bodies are made up of about 60 trillion cells. Each one of those cells manufactures proteins. The kinds of proteins any given cell makes determine its particular characteristics, which in turn create the characteristics of the entire body.

The instructions for making these proteins are stored in chemicals or molecules called DNA, which is organized into chromosomes. Chromosomes are found in the center, or nucleus, of all of our cells, including the eggs and sperm.

Chromosomes are passed down from generation to generation through the egg and sperm. Typically, we all have 46 chromosomes in our cells, two of which are sex chromosomes. In females, these are two Xs; in males they are an X and a Y.

The Role of Genes?

Genes are sections of DNA that are passed from generation to generation and perform one function. If we think of DNA as letters in the alphabet, the genes are words and the chromosome is a full sentence. All 46 chromosomes then make up the whole book.

There are many genes on each chromosome; we all have tens of thousands of genes that instruct our bodies on how to develop.

Genes are given names to identify them and the gene responsible for Fragile X syndrome is called FMR1. The FMR1 Gene is on the X chromosome.

How Do Changes in the FMR1 Gene Lead to FXS?

The FMR1 gene appears in four forms that are defined by the number of repeats of a pattern of DNA called CGG repeats.

Individuals with less than 45 CGG repeats have a normal FMR1 gene. Those with 45-54 CGG repeats have what is called an “intermediate” or “grey zone allele,” which does not cause any of the known Fragile X associated disorders.

Individuals with 55-200 CGG repeats have a “premutation,” which means they carry an unstable mutation of the gene that can expand in future generations and thus cause Fragile X syndrome in their children or grandchildren. Individuals with a premutation can also develop FXTAS or FXPOI themselves.

Individuals with over 200 CGG repeats have a full mutation of the FMR1 gene, which causes Fragile X syndrome.

The full mutation causes the FMR1 gene to shut down or “methylate” in one region. Normally, the FMR1 gene produces an important protein called FMRP. When the gene is turned off, the individual does not make this protein. The lack of this specific protein is what causes Fragile X syndrome.

The Fragile X Premutation

Fragile X-associated Disorders are a group of conditions called trinucleotide repeat disorders. A common feature of these conditions is that the gene can change sizes over generations, becoming more unstable, and thus the conditions may occur more frequently or severely in subsequent generations. These conditions are often caused by a gene change that begins with a premutation and then expands to a full mutation in subsequent generations.

Approximately 1 in 151 females and 1 in 468 males carry the FMR1 premutation. They are thus “carriers” of the premutation.

Premutations are defined as having 55-200 CGG repeats and can occur in both males and females. When a father passes the premutation on to his daughters, it usually does not expand to a full mutation. A man never passes the Fragile X gene to his sons, since he passes only his Y chromosome to them, which does not contain a Fragile X gene.

A female with the FMR1 premutation will often pass on a larger version of the mutation to her children (more on this point below). She also has a 50 percent chance of passing on her normal X chromosome in each pregnancy, since usually only one of her X chromosomes has the FMR1 mutation.

The chance of the premutation expanding to a full mutation is related to the size of the mother’s premutation. The larger the mother’s CGG repeat number, the higher the chance that it will expand to a full mutation if it is passed on.

Typically, the premutation has no immediate and observable impact on a person’s appearance or health. However, some females with a premutation will experience Fragile X-associated primary ovarian insufficiency (FXPOI), which causes infertility, irregular or missed menstrual cycles, and/or early menopause.

Additionally, some older adults with a premutation may develop a neurological condition called FXTAS, (Fragile X-associated tremor/ataxia syndrome), an adult onset neurodegenerative disorder.

FXTAS and FXPOI are part of the family of conditions called Fragile X-associated Disorders.

The FMR1 Full Mutation

A full mutation is defined as having over 200 CGG repeats and causes that indicate the presence of Fragile X syndrome in males and some females. Most full mutation expansions have some degree of Methylation (the process which “turns off” the gene). Males with a full mutation will have Fragile X Syndrome, though with varying degrees of severity

About 65-70 percent of females with a full mutation exhibit some difficulties with cognitive, learning, behavioral, or social functioning, and may also have some of the physical features of FXS (such as large ears or a long face). The remaining 30-35 percent are at risk to develop mental health issues such as anxiety or depression, or they may have no observable effects of the full mutation.


Fragile X in an “X-linked” condition, which means that the gene is on the X chromosome.

Since a woman has two X chromosomes a woman with a premutation or full mutation has a 50% chance of passing on the X with the mutation in each pregnancy, and a 50% chance of passing on her normal X.

If she has a premutation, and it is passed on (to either males or females), it can remain a premutation or it can expand to a full mutation. If she has a full mutation and it is passed on (to either males or females), it will remain a full mutation.

Because males have only one X chromosome, fathers who carry the premutation will pass it on to all their daughters and none of their sons (they pass their Y chromosome on to their sons). There have been no reports of premutations that are passed from a father to his daughter expanding to a full mutation. This appears to only occur when passed from a mother to her children.

Unique Features of Fragile X Inheritance

In many X-linked conditions only males who inherit the abnormal gene are affected. Fragile X syndrome is one of the X-linked conditions that can also affect females.

Additionally, in other X-linked conditions all males who carry the abnormal form of the gene are affected. In Fragile X syndrome, unaffected males can carry the gene in the premutation form while themselves having no symptoms of the condition.

What Is a Gene?

A gene is a unit of heredity that is passed down from parent to child. Genes are located on chromosomes that are in all of our cells, including the sperm and egg that make a baby.

What Is a Gene Made Of?

Genes are made of molecules or chemicals called DNA. The pattern of DNA will determine if the gene is working properly. The DNA has to be in a certain pattern or order, like the numbers in a phone number.

How Does a Gene Work?

A gene has different parts that work together like a factory or machine. It has a “promoter” that turns the gene on, like a light switch. It has sections that are just “filler” and act as place holders, called “introns.” The sections that are used to make a protein or do a job are called “exons.”

What Do Genes Do?

The job of a gene is to either make a protein, the building blocks of all the structures in the body, or to regulate other proteins in the body.

How Does a Gene Make Proteins?

The DNA in the gene is a code that is “transcribed” or “talks” to another kind of molecule called RNA. This is like one side of Velcro sticking to another that it matches up to. The RNA then “translates” the DNA to put together the protein.

Now that you understand what genes are, let’s discuss the Fragile X gene…

The Fragile X (FMR1) Gene

Why Is It Called the FMR1 Gene?

Genes are named when they are discovered. Often the name isn’t exactly the same as the condition, in case it is later discovered that there is more than one gene involved in the condition. The gene that causes Fragile X is called the “FMR1 gene,” which stands for Fragile X mental retardation gene. Though the term “mental retardation” has given way in recent years to the more generally accepted term of “intellectual disabilities,” the scientific name of the gene can’t change with the times.

Ideogram of X chromosome

Where Is the FMR1 Gene Located?

The FMR1 gene is located on the X chromosome. We all have 46 chromosomes in all of our cells, 44 of which are numbered 1-22 in pairs. Then females have two X chromosomes and males have one X and one Y chromosome. Each chromosome has two arms, one called the “p” arm (the short arm) and one called the “q” arm (the long arm).

There are many genes on each chromosome, like houses on a street. Each gene is given an address, depending on where it lies on the chromosome. The address of the FMR1 gene is Xq27.3

Does Everyone Have an FMR1 Gene?

Yes, everyone has an FMR1 gene. When someone states, “I have the gene for Fragile X,” they really mean they have a gene mutation for Fragile X. Some Fragile X genes are normal and some are not.

What Does the FMR1 Gene Do?

The FMR1 gene makes a very important protein called FMRP (Fragile X mental retardation protein). Though this protein is found in all our cells, it is most abundant in the nerve cells, and particularly in a part of the nerve cell that “talks” to other nerve cells called “dendrites.”

What Is an FMR1 Gene Mutation?

A mutation is any change in a gene. Some mutations don’t cause any problems and we don’t know about them (unless found in the laboratory). Mutations in the FMR1 gene involve an abnormal expansion of the DNA in the “promoter” area of the gene. Often a mutation causes decreased or absent protein production. In individuals with a “full mutation,” their FMR1 gene is shut down and they don’t make enough or any FMRP.

Are There Different Kinds of FMR1 Mutations?

Yes. An individual can have a normal FMR1 gene, a “premutation” or a “full mutation.” There is also another category called an “intermediate allele,” which is not a true mutation, but an expansion somewhere between the “normal” FMR1 gene and the premutation.

What Is the Difference Between These Mutations?

FMR1 Gene Categories

The mutation of the FMR1 gene involves a repeating pattern of DNA called a “CGG repeat.” DNA is made of molecules that are abbreviated A, C, G and T. A CGG repeat in the FMR1 gene is a pattern of DNA that may repeats itself anywhere from 30 to 1000 times. In the FMR1 gene there is an area of the promoter that is rich in these CGG repeats and is measured when Fragile X testing is performed.

In this area, there is normally about 30 repeats of CGG. In individuals with the premutation, there are from 55-200 of these repeats. Persons with the full mutation have more than 200 of the CGG repeats. When there is more than 200 CGG repeats, the gene is turned off by a process called Methylation.

Methylation happens to other genes too, when they are supposed to be turned off (as in the genes we don’t use, like those that make a tail grow!). In Fragile X the methylation turns off the FMR1 gene, so no FMRP is produced. This is what causes Fragile X Syndrome.

Each cell works somewhat like a factory. The external membrane functions as the exterior walls of the factory. The nucleus stores the genetic blueprints in the form of DNA. The machinery (ribosomes) for assembling the products (proteins) is attached to the shop floor (endoplasmic reticulum). The Golgi concentrates the proteins to export them. The lysosome is used for waste disposal and recycling.

What Do Proteins Do?

Used with permission of Paul Thiessen Chemical Graphics

The body makes about 50,000 different kinds of protein. These proteins serve in two major roles. Some of them make up part of the structure of our bodies. Others are enzymes. An enzyme is a protein that works like a tool. It helps a particular chemical reaction take place.

For example, there is a particular enzyme that breaks apart starch into sugar molecules; you use it in your small intestine to digest your carbohydrates. Another enzyme takes a sugar molecule and adds a phosphate onto it to make it unstable. Then a series of about 20 more enzymes each process the unstable sugar molecule in a disassembly line that pulls the sugar molecule apart and releases energy.

Proteins are made out of 20 different amino acids like leucine, lysine, tryptophan, etc. When you eat foods that contain proteins, the first thing your digestive system does is to break them down into amino acids. Then you assemble those amino acids into your own proteins. In a way, it is like words. You can make all kinds of words out of 26 letters. You could take a magazine, cut apart all of the letters and reassemble them into your own words. The proteins you make are assembled out of the parts from the proteins you digested from your food.

Fragile X syndrome is caused because people with the disease don’t make a particular protein, FMRP. Sometimes someone asks why we can’t just feed a person with Fragile X more protein.
The problem is not lack of protein; a bunch of proteins won’t help someone who is missing FMRP. It is a specific protein that is missing, not proteins in general.

To understand this, think about someone who is trying to say the word “frozen”. Handing the person a list of names from the phone book won’t help. In the same way, having someone eat a bunch of proteins won’t give the person the specific protein that is needed.

Even if we injected that person with lots of FMRP, it would not help. FMRP needs to be present in the right cells at the right time in the right amount.

We are just beginning to learn which cells normally make FMRP. We have some clues about what the function of FMRP is but we have much to learn.

Used with Permission of Dennis Kunkel’s Image Gallery

The synthesis of a protein such as FMRP (Fragile X mental retardation protein) begins in the nucleus of the cell when the DNA receives a request for that specific information. It is a bit like someone going to a library and selecting a particular book. In response to the request, the DNA opens up and a copy of the coded information is transcribed, much like someone photocopies a chapter of a book in a library. That copy of the DNA is called messenger RNA (mRNA).

The mRNA leaves the nucleus and goes out to the main part of the cell, the cytoplasm. There the coded mRNA is translated on ribosomes with the help of transfer RNA and a protein is assembled out of amino acids.

The protein takes on a particular shape that allows it to perform very specific tasks. While we know the tasks of some of the proteins that humans make, we only have hints about the role of FMRP.

Used with permission of New England Biolabs

One of the ways the cells control which genetic information they will use is to chemically modify the DNA. The illustration on the left shows an enzyme (diagrammed in ribbons) adding methyl groups to some of the DNA (balls in the form of a double helix). This inactivates that part of the chromosome. It’s as if we were to put glue on the edges of some of the books in the library; those pages would become unavailable to readers.

Good methylation

In females methylation is used regularly to solve a problem. Men have only one X chromosome and women have two. As a result, female cells might be expected to make twice as much protein from the information on X chromosomes as males do. Instead, women’s cells randomly pick one of the X chromosomes and turn it off by methylation. Thus both males and females have one working X chromosome in each cell and as a result, one working unit of all the genetic information on the X chromosome.

Bad methylation

As noted above, methylation is generally a useful method for turning off chromosomal information. However, in Fragile X syndrome, methylation is involved in causing the disease. Near the FMR1 Gene is a regulatory site called a CpG island. In most people, the site is not methylated. As a result, the cell can use the FMR1 gene when there is a need for FMRP – The Fragile X Protein.

In people with Fragile X syndrome, the CpG island is methylated. As a result, the cell is unable to copy the information in the FMR1 gene. Since an mRNA copy is not made, FMRP will not be synthesized. Since there is no FMRP at the time and place it is needed, the characteristics of Fragile X syndrome are set in motion.

It’s not really the CGG’s

Much of the focus on Fragile X syndrome is on the expansion of the repeated CGG’s. It is technically not the expansion that directly causes the problem. Instead, having more than 230 CGG repeats sets in motion methylation of part of the FMR1 gene. The methylation stops the synthesis of FMRP and the absence of FMRP causes Fragile X syndrome. We do not know why having too many CGG repeats triggers methylation.

In theory, if the methylation could be removed from that spot on the FMR1 gene, it could allow access to the FMR1 gene and allow its FMRP product to be assembled. This is one of the potential treatment areas that researchers are investigating.

Mosaic females

The inactivation of female X chromosomes by methylation mentioned above, also seems to partially determine the impact of a full Fragile X mutation on females. Each cell in a female will inactivate or turn off one of its two X chromosomes.

If a large proportion of the cells turn off the X chromosome with the Fragile X mutation, then most of the cells will have an active X chromosome that can produce FMRP. As a result, the impact of Fragile X syndrome will be limited.

If a large proportion of the cells turn off the X chromosome with the working FMR1, then there will be few cells able to produce FMRP. As a result, the impact of Fragile X syndrome will be more pronounced.

So the severity of Fragile X syndrome on a female depends in part on whether her cells turn off mainly X chromosomes with a good FMR1 or mainly X chromosomes with a defective FMR1.

What Does a Genetic Counselor Do?

A genetic counselor is a trained master’s level medical professional who works with individuals and families to:

  • Review genetic testing and diagnoses.
  • Review inheritance patterns.
  • Help identify possible carriers in the family.
  • Discuss the symptoms and features of Fragile X-associated Disorders.
  • When appropriate, review reproductive issues and options.
  • Make referrals and provide professional and emotional support.

Due to the complexity of Fragile X testing, the counselor is essential in the interpretation of results and for providing accurate information regarding Fragile X.

Where Do Genetic Counselors Work?

Genetic counselors can work either independently or are part of a medical team.

Some common settings where genetic counselors work are:

  • Medical genetics departments in a hospital/medical center setting.
  • Prenatal, perinatal or infertility care providers.
  • Specialist medical groups such as oncology, hematology, neurology, cardiology.
  • Multidisciplinary clinics such as craniofacial, skeletal dysplasia, Fragile X clinics.
  • Private practice.
  • Public and community health settings.
  • Genetics laboratories.
  • Support organizations (such as the NFXF).

Who Should Meet With a Genetic Counselor?

Anyone who:

  • Has been identified as being a “Fragile X carrier” or has positive, inconclusive or, in any way unusual Fragile X testing results.
  • Has a family member who has been identified as being a carrier of a Fragile X mutation.
  • Has a child or family member diagnosed with Fragile X syndrome or any of the Fragile X-associated Disorders.
  • Has a family or personal  history of undiagnosed intellectual disabilities, autism or learning disorders.
  • Has symptoms of any of the Fragile X-associated Disorders, including infertility, early menopause and/or adult onset neurological or movement disorders.

What Will Likely Occur in a Genetic Counseling Session?

The counselor:

  • Will ask questions regarding the  medical or developmental/learning history of your family members (including children, parents, brothers and sisters, aunts and uncles, cousins, nieces and nephews, grandparents).
  • Will review the genetic implications of the diagnosis or test results.
  • May identify other family members who may have inherited the gene mutation.
  • May make suggestions or assist with informing or contacting family members regarding testing.
  •  May meet with you either independently or in conjunction with a medical geneticist or other provider, who will likely examine your child or affected family member. If the counseling will be focused on carrier testing, an exam is often not indicated.
  • Can work with you and other family members to coordinate testing throughout the family.
  • Can provide information and help with decision-making regarding reproductive issues and options and coordinate/arrange any further testing.
  • Can make referrals to other providers for medical evaluations and care, prenatal care and  testing, therapies for your child, family counseling, or whatever needs you have at the time.

How Do You Find a Genetic Counselor in Your Area?

Most of us have heard of CGG repeats, those patterns of DNA molecules that are counted when testing for Fragile X (FMR1) mutations. (For background, see the Q & A with Dr. Karen Usdin on page 16.) We then hear a number like 400 for full mutations or 80 for premutations and that’s it, nothing else matters but that magic number. We envision a long tract of CGGCGGCGGCGG over and over again, as the genetic counselor or doctor described. But lately you may also have begun hearing about “AGG interruptions,” which in some way are related to Fragile X inheritance. This article will offer an overview of their importance.

To review some genetics, DNA is a strand of chemicals, called nucleotides. The nucleotides that make up DNA are Adenine, Thymine, Cytosine and Guanine (abbreviated as A, T, C and G). So a CGG repeat is a triplet of cytosine, guanine and guanine. The pattern of nucleotides (like ATCGATCG, etc.) makes up a gene that instructs the cell on how to make or regulate proteins.

In the 1990s, after the discovery of the FMR1 gene and the CGG repeat expansion that causes Fragile X syndrome, Fragile X experts began talking about a different DNA pattern called an “AGG interruption,” which occurs between about every nine or 10 CGGs. In the normal Fragile X gene (five to 45 repeats), you might have a 30-CGG-repeat pattern that has 10 CGGs, one AGG, then 10 CGGs, then one AGG, then another 10 CGGs. These AGG interruptions act as a sort of anchor, keeping the 30-repeat FMR1 gene stable, like fence posts every 10 feet in a long fence.

As DNA samples were being studied by Fragile X researchers, they found that while some individuals had AGG interruptions every nine or 10 CGG repeats, some lost them as the repeats got bigger. So a person might have 10 CGGs then one AGG, 10 CGGs then one AGG, then 40 CGGs in an individual who has 60 CGG repeats.

This led to two questions regarding the presence or pattern of AGG interruptions: 1) Do the number or placement of AGG interruptions affect the stability of the FMR1 gene?
2) “Why do some premutations expand and some not?”

A recent study by Dr. Sarah Nolin at Institute of Basic Research in New York, Dr. Elizabeth Berry-Kravis at Rush Medical Center in Chicago and Asuragen Inc. in
Austin, Texas was presented in a poster at the annual meeting of the American College on Medical Genetics earlier this year. The purpose of the study was to see how AGG interruptions affect the stability of the premutation, and also to develop (and use) the technology that would identify these AGG interruptions in Fragile X testing.

The study found that if there were 33 or fewer CGGs in a row beyond the last AGG, then the premutation usually didn’t expand. But when there were 39 or more CGGs in a row after the last AGG, without any AGG interruptions, then the premutation was usually unstable (expanding by one or more CGG repeats). This helps us understand why some premutations with, for example, 62 CGG repeats, appear stable over generations, whereas some with the same number of 62 repeats expand over subsequent generations. It’s because the one with a long tract (>39 repeats) of CGG repeats without an
AGG “anchor” is more likely to expand than one with properly interspersed AGG interruptions.

The technology that was developed to identify the presence and placement of the AGG interruptions is new and exciting. Asuragen, in cooperation with the UC Davis M.I.N.D.
Institute, has developed a unique type of PC test (see below) called “Amplidex.” It can identify the AGG interruptions in both males and females and in both normal and expanded FMR1 genes.

For scientific reasons, labs have had a hard time finding AGG interruptions, especially in women. This new technology overcomes these hurdles. Variations on a genetic testing method called polymerase chain reaction, or PCR, reveal the number and location of AGG interruptions. Three different PCR studies done together show very different patterns of the CGG repeat region when AGG interruptions are present. Specially trained experts in a laboratory can review all three studies to solve the problem of where the AGG interruptions are located; the method is similar to solving a brainteaser puzzle.

This test is currently available only for research studies. Eventually it may be available for clinical use. So it is possible that in addition to the “magic number” of CGG repeats, the presence and placement of AGG interruptions will inform your risk for expansion of a premutation.

Why it Matters

There are a number of reasons why this issue of AGG interruptions is important.

First, if you or a family member have a premutation that hasn’t expanded to a full mutation, this technology may give you more accurate risk figures for that premutation to expand.

Second, it is possible that the number of AGG interruptions may contribute to or affect the risk for FXPOI or FXTAS. The risk for FXPOI is about 20–25 percent in female premutation carriers; the risk for FXTAS is about 30–40 percent in male and 5–8 percent in female carriers. At this point we don’t have good “predictors” of who may develop these two conditions. It is possible that this technology identifying AGG interruptions may lead us to better predict the group at highest (and lowest) risk for these Fragile X-associated Disorders.

Third, it is possible that our knowledge of AGG interruptions might lead to better understanding of the small subset of children with premutations who have developmental disorders like autism, ADHD, etc. We know this is clearly a small group, since most premutation carriers exhibit normal development and cognitive function. However, there is a small subset of (mostly male) children in the premutation range who have developmental/behavioral disorders, and this new technology might give us some clues as to why they are affected, even though most carriers are not.

All of which leads to the possibility that you may soon hear, “I have 65 repeats with three AGG interruptions, ya-hoo!”