July 22, 2022 is World Fragile X Syndrome Day, designated by the United States Congress in 2000 to raise awareness about Fragile X syndrome, the benefits of early diagnosis and to advocate for more research funding for treatment.
What is Fragile X Syndrome?
Fragile X syndrome (FXS) is one of the most common causes of inherited intellectual disability due to a single gene; however it is still quite rare, occurring in about 1 out of every 4,000 males and 1 out of every 8,000 females.
FXS is caused by a repeat expansion of the FMR1 gene, and is inherited in an X-linked pattern. The FMR1 gene makes a protein called FMRP. The FMRP gene, when working properly, helps to develop synapses in the brain. Inherited mutations in the FMR1 gene can impair the ability to make a functional FMRP protein which can lead to the symptoms of Fragile X. Features of FXS include developmental delay and intellectual disability, features of autism spectrum disorder, characteristic facial features, joint laxity, scoliosis, recurrent ear infections and other medical concerns.
The FMR1 gene is located on the X chromosome. Females typically have two X chromosomes and males have one (they have a Y chromosome instead of a second X chromosome), which is why it is more common to see males affected with FXS than females (females basically have a back-up copy of the FMR1 gene, while males don’t). While females can be similarly affected, they are usually less severely affected than males if they show any signs or symptoms at all.
The FMR1 gene has a section where three DNA building blocks (CGG, called a trinucleotide repeat) are repeated over and over. Everyone has these repeats in their FMR1 gene, but how many repeats the gene has is important. Most people have between 5 and 40 CGG repeats in their FMR1 gene. People who have FXS have over 200 CGG repeats (called a full mutation). Having >200 CGG repeats causes the FMRP protein that the gene makes to not work how it’s supposed to. Not having enough of this working FMRP protein is what leads to the signs and symptoms of FXS.
The number of CGG repeats that someone’s FMR1 gene has can increase (called an expansion) when it is passed down and is much more likely to expand when passed on from the egg, than it is through the sperm. For example, a mother could have one of her X chromosomes that has an FMR1 gene with 80 CGG repeats, but then when she passes it down to her daughter, it expands to 120 CGG repeats. It is less common for the expansion to happen when the FMR1 gene is passed down from someone’s father. Generally the instability gene increases as the number of the CGG repeats expands and presence of AGG interruptions. This means that the number of repeats can increase from generation to generation, especially when passed on through the egg.
The smallest number of repeats that has expanded to a mutation (200 CGG repeats) is 56. Because of this, if someone has an FMR1 gene with between 55 and 200 CGG repeats, they are called a premutation carrier. FMR1 genes that have between 45 and 55 CGG repeats are called intermediate.
The FMR1 gene in premutation carriers is still able to make FMRP protein, so they are not at risk to have FXS. However, individuals who have a premutation can be at a higher risk for Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). Women who are premutation carriers are also at increased risk for FMR1-Related Primary Ovarian Insufficiency (FXPOI). Those with premutations have also reported other symptoms such as autoimmune related disorders, depression and other psychiatric or behavioral disorders, neuropathies, migraines, and other symptoms that are not as well understood.
|FMR1 Gene||Number of CGG repeats||Expected Outcome|
|Typical allele||<44||Allele is stable – unlikely to change much from generation to generation|
|Intermediate allele||45-54||Somewhat unstable – may increase slightly; not expected to expand to full mutation within one generation|
|Permutations||55-200||More unstable than intermediate alleles – can expand from generation to generation to a full mutation|
|Full Mutation||>200||Expected to cause Fragile X syndrome in individuals with one X chromosomes and may cause symptoms in individuals with two X chromosomes|
Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
FXTAS is a condition characterized by tremors (trembling or shaking) and ataxia (movement, coordination, and balance difficulties). Individuals with FXTAS can also have problems with involuntary body functions (such as bladder and bowel movement control) as well as mental health issues (depression, anxiety, mood changes, etc). Average age of onset of symptoms for FXTAS is typically between 60 to 65 years of age. Males also have a higher risk for FXTAS than women (40% compared to 16-20% for women), and tend to be more severely affected.
FMR1-Related Primary Ovarian Insufficiency (FXPOI)
FXPOI is characterized by a woman going through menopause (stopping of periods) before the age of 40.. Women in the general population have about a 1% risk for primary ovarian insufficiency, while women who carry a premutation have about a 20% risk. Women with FXPOI go through menopause an average of five years earlier than women without FXPOI.
Individuals who have an intermediate FMR1 gene (45-55 CGG repeats) are not considered to be carriers, and not at risk for FXTAS or FXPOI. There have been some studies that suggest a potential increased risk for developmental or behavioral disorders, but this remains uncertain and is likely unrelated.
Diagnosing Fragile X Syndrome
The diagnosis of FXS is made through genetic testing that looks at the number of CGG repeats that are in the FMR1 gene. If a male has over 200 CGG repeats in his FMR1 gene, then he has a diagnosis of FXS. If a female has over 200 CGG repeats in one of her FMR1 genes, then she is a carrier for FXS and may experience some symptoms. If a female has over 200 CGG repeats on BOTH of her FMR1 genes, then she has a diagnosis of FXS. FXTAS and FXPOI are diagnosed by a combination of clinical symptoms and having between 55-200 CGG repeats in their FMR1 gene.
Genetic Testing for Fragile X Syndrome
Genetic testing for Fragile X syndrome is often recommended for individuals who have intellectual/cognitive disability, developmental delay (where the cause is unknown), or autism spectrum disorder. Individuals with personal or family histories of FXS-related health issues (late onset tremor or ataxia of unknown cause, early menopause) may also wish to consider fragile X syndrome screening.
Carrier screening is quite commonly offered to individuals who are considering pregnancy or who are pregnant, however currently, the American College of Obstetricians and Gynecologists recommends carrier screening for Fragile X syndrome only if there is a history of intellectual disability, autism or premature ovarian insufficiency on the maternal side of the family.
If you have questions about Fragile X syndrome or carrier testing you have had, it may be helpful to speak with a genetic counselor. Understanding what these results could mean for you and your family can be complicated and we can help sort through all of the information in the context of your own unique situation. Contact us or schedule an appointment on our website.