The Science of Fragile X
Here, you’ll find comprehensive information about Fragile X Syndrome, from its scientific foundations to treatment recommendations. Our goal is to empower you with knowledge, foster understanding, and connect you with the resources you need to support individuals and families affected by Fragile X
Everyone has the FMR1 gene
(Fragile X Messenger Ribonucleoprotein 1)
This gene is found on the X chromosome, one of the building blocks of our DNA. Changes or expansions in this gene can lead to different challenges in learning or behaviour, as well as physical symptoms that may look a bit different for each person. These Fragile X-associated conditions are a group of inherited health conditions caused by changes in a specific gene called the FMR1 gene. These conditions can affect family members in various ways, and each person's experience is unique.
Approximately 136,000 Canadians are impacted by Fragile X
due to the expansion of theFMR1 gene
Fragile X syndrome
Fragile X syndrome is the most common form of inherited intellectual and developmental disability.
It is estimated that Fragile X syndrome affects
1 in 4,000 males and 1 in 6,000 females
Fragile X Premutation carriers
Both males and females who have the Fragile X gene expansion are known as premutation carriers.
About 1 in 250 women and 1 in 800 men are Fragile X premutation carriers.
The Fragile X Gene and Protein
This gene is located on the X chromosome and plays a critical role in brain development. This gene contains a repeating sequence of three DNA building blocks—cytosine (C), guanine (G), and guanine (G), known as CGG repeats.
The FMR1 Gene:
Everyone has the FMR1 gene
Normal Range (5-44 repeats)
In this range, the FMR1 gene functions as expected and produces a protein called FMRP, which is essential for brain development and function. People with CGG repeats in the normal range are not affected by Fragile X-associated conditions.
Intermediate (or "Gray Zone") Range
This range is often called the "gray zone" because it doesn’t typically cause health issues. People with repeats in this range are unlikely to experience Fragile X-associated conditions or pass on the condition to their children, but there may be a slight risk of the gene expanding in future generations.
Premutation Range
People with 55-200 CGG repeats are considered carriers of a premutation. While they may not have Fragile X Syndrome (FXS), they can develop related conditions, such as FXTAS (a movement disorder) or FXPOI (which affects ovarian function in females). Carriers are also at risk of passing an expanded gene to their children, which may result in FXS.
Full Mutation
When the FMR1 gene has a change or expanded mutation where the CGG repeats grows too large and expands with over 200 repeats. This expansion leads to what is known as the full mutation of Fragile X syndrome, causing the gene to stop working as it should. When the gene is not working, it cannot produce enough of a vital protein called FMRP.
The Function of FMRP:
A key to brain development
The FMR1 gene is responsible for making a protein called FMRP (Fragile X messenger ribonucleoprotein). FMRP is important for brain development and helping brain cells (neurons) communicate to each other.
When FMRP is absent or or there is limited production due to the FMR1 gene mutation:
Synaptic Plasticity (the brain’s ability to strengthen or weaken connections between neurons) is impaired, making it harder for the brain to process and store information.
Neuronal Overactivity: Without FMRP, the brain's normal communication systems become overactive, leading to challenges with learning, behaviour, and sensory processing.
In simple terms: FMRP helps brain cells "talk" to each other, and when it’s missing, this communication breaks down, leading to the learning and behavioural issues seen in Fragile X Syndrome.
The Scientific Lens
Signs and Symptoms
When exploring Fragile X syndrome through a scientific lens, we focus on the observable traits, or phenotypes, that help us understand the condition's full impact. These traits include cognitive and developmental challenges, behavioural difficulties, and emotional regulation issues. By studying these deficits, we can identify patterns of development and target interventions that improve quality of life. Focusing on these observable characteristics allows researchers and clinicians to develop better diagnostic tools, treatments, and support strategies, which are critical for addressing the unique needs of individuals with Fragile X syndrome.
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Individuals with Fragile X syndrome may have learning disabilities, intellectual disabilities, and developmental delays. Challenges with abstract thinking, short-term memory, and problem-solving are common.
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People with Fragile X syndrome may exhibit anxiety, hyperactivity, social withdrawal, impulsiveness, and repetitive behaviors. They often struggle with transitions and may become easily overwhelmed in social or sensory-stimulating situations.
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While many individuals with Fragile X syndrome are friendly and have a strong desire for social interaction, they may experience challenges with eye contact, social anxiety, and delayed speech and language development.
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Many individuals with Fragile X syndrome are sensitive to light, sound, touch, or other sensory stimuli. This can lead to sensory overload, making it difficult to focus or stay calm in certain environments.
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Some individuals with Fragile X may have physical characteristics such as a long face, prominent ears, and flexible joints.
Fragile X Associated Conditions
An associated condition in Fragile X refers to a health issue linked to specific changes in the FMR1 gene. These conditions can affect people in different ways, often impacting areas such as learning, movement, fertility, and emotional well-being. While some associated conditions appear early in life, others may develop later, even in adulthood. Each associated condition is unique, but they all stem from variations in the same gene, which means that multiple family members may experience related symptoms or health challenges in their own ways
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Description: FXTAS primarily affects adults, often those over 50 who carry a premutation of the FMR1 gene. It is a neurological condition that can cause issues with movement and coordination.
Common Symptoms: Symptoms may include tremors, balance problems (ataxia), memory loss, mood changes, and sometimes difficulty with everyday tasks.
Who It Affects: FXTAS mainly affects male carriers but can also impact female carriers, though typically to a lesser extent.
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Description: FXPOI affects women who carry the FMR1 premutation and can lead to reduced function of the ovaries before age 40, impacting fertility and hormone levels.
Common Symptoms: Women with FXPOI may experience irregular menstrual cycles, early menopause, and symptoms related to low estrogen, such as hot flashes and bone density loss.
Who It Affects: FXPOI affects female carriers of the FMR1 premutation.
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Description: FXAND is a broader term for a set of mental health and behavioral issues that can appear in individuals with the FMR1 premutation. These issues may include anxiety, depression, mood swings, ADHD, and social challenges.
Common Symptoms: Anxiety, depression, mood regulation challenges, and difficulties with attention and social interactions are common for individuals with FXAND.
Who It Affects: FXAND can affect both male and female carriers of the FMR1 premutation, and symptoms can vary widely.
“But he does not look like he has Fragile X”
“But he does not look like he has Fragile X”
"We won't test until there are symptoms, even though his brother has full mutation Fragile X."
"We won't test until there are symptoms, even though his brother has full mutation Fragile X."
" He doesn't fit the behavioural profile.”
" He doesn't fit the behavioural profile.”
Diagnostic Process
The process of diagnosing Fragile X syndrome typically involves several steps, from observing early developmental signs to genetic testing. Here's a breakdown of the process:
Observation of Early Signs
Early signs may include developmental delays, speech and language difficulties, and behavioural challenges like hyperactivity or anxiety. Families often notice these signs in infancy or early childhood.
Consultation with a Healthcare Professional
Parents usually consult with their child’s family doctor or paediatrician about developmental concerns. If Fragile X is suspected, a referral to a geneticist or neurologist may be made for further evaluation.
Genetic Testing
The definitive way to diagnose FXS is through a DNA blood test, known as a Fragile X DNA test. This test looks for mutations in the FMR1 gene. The test can confirm if an individual has the full mutation, premutation, or normal FMR1 gene.
Post-Diagnosis Counselling
After a diagnosis, families typically receive genetic counselling to understand the condition better, discuss possible interventions, and connect with support resources.
While Fragile X has always been with us, the discovery of its cause and the test for it are relatively new, and so not every doctor will be familiar with the condition or the test for it.
We have created a document you may use when discussing Fragile X and testing for it with your physician https://www.fragilexcanada.ca/wp-content/uploads/2022/05/onepager.pdf.
Ordering First-Tier Genetic Testing
Neurodevelopmental disorders are a group of conditions which include autism, global developmental delay and intellectual disability, as well as attention deficit hyperactivity disorder, specific learning disorders, and others.
An neurodevelopmental disorder may have a genetic cause, such as a genetic syndrome, or complex inheritance with genetic susceptibility factors. An identifiable genetic etiology is more likely in those with co-occurring health conditions or those who have a family history of NDDs.
Genetic testing is indicated for all:
autistic individuals.
individuals with unexplained GDD and/or ID.
individuals with an NDD and co-occurring features suggestive of a possible genetic condition.
The Canadian College of Medical Geneticists 2023 Position Statement recommends first-tier genetic testing be organized by non-genetics clinicians before or concurrent with a referral to genetics. This includes chromosomal microarray and, in some cases, Fragile X syndrome testing.
Point of Care Tools
First-tier genetic testing can be ordered by any physician in:
Maritimes (Newbrunswick, Nova Scotia, Prince Edward Island)
First-tier genetic testing can only be ordered by a Geneticist or Specialist
(e.g. developmental paediatrician) in:
Newfoundland and Labrador (geneticist only)
GECKO (Genetics Education Canada: Knowledge Organization)