Genetics & Inheritance
Fragile X-associated disorders include a wide range of physical, intellectual, and behavioral symptoms that can affect family members in many different ways. These conditions are passed down in families through expansions of the FMR1 gene. Even for genetics professionals, FMR1 inheritance is complex and confusing, so it’s no surprise that families often have questions about the genetics of Fragile X. We’ll start here with some background on genetics and 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.
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 (cell).
There are many genes on each chromosome; we all have 10s of thousands of genes that instruct our bodies on how to develop. Genes are located on chromosomes that are in all of our cells, including the sperm and egg that make a baby.
DNA is the material that is located in the cell’s nucleus that makes up the chromosomes and genes. 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 Do Genes 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 placeholders, 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.
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.
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.
How Does the FMR1 Gene Cause FXS?
The FMR1 gene appears in four forms that are defined by the number of repeats of a pattern of DNA called CGG repeats. 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 1,000 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.
- Normal: Individuals with less than 45 CGG repeats have a normal FMR1 gene.
- Intermediate: 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.
- Premutation: 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.
- Full Mutation: 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. 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!).
Normally, the FMR1 gene produces an important protein called FMRP. When the gene is turned off, the individual does not make this protein. In Fragile X the methylation turns off the FMR1 gene, so no FMRP is produced.
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 male passes the premutation on to his daughters, it usually does not expand to a full mutation.
- A male 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% 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 Fragile X-associated tremor/ataxia syndrome (FXTAS), 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% 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% 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.
Most of us have heard of CGG repeats, those patterns of DNA molecules that are counted when testing for Fragile X (FMR1) mutations. 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.