Fragile X (FMR1) Genetic Testing

Genetic testing is used to evaluate the FMR1 gene and determine the number of CGG triplet repeats that are present. Testing is used to:

• Diagnose fragile X syndrome and FMR1-related conditions molecular testing for an abnormal FMR1 gene is the only way to diagnose fragile X syndrome.
• Determine whether you are a carrier of a FMR1 premutation or full mutation and determine the risk of passing any genetic variants to your children
• Diagnose fragile X syndrome or an FMR1-related condition in your fetus (prenatal diagnosis); prenatal diagnosis for fragile-X syndrome is not routine. The American College of Obstetricians and Gynecologists recommends it only for women who are known carriers of the FMR1 premutation.

A genetic test for fragile X syndrome may be ordered when:

• Your child has signs and symptoms of an autism spectrum disorder (ASD), intellectual disability, or developmental delay, especially if you have signs and symptoms related to fragile X syndrome, a family history of fragile X syndrome, or relatives with intellectual or developmental disabilities and the causes have not been identified
• You are an adult with later-in-life onset of symptoms such as tremors or lack of muscle control or coordination, especially if you also have a family history of movement disorders, fragile X syndrome, or intellectual or developmental disabilities with unidentified causes
• You are a woman with fertility problems linked to elevated follicle stimulating hormone (FSH) levels, especially if you have female relatives whose ovaries stopped working at a young age (premature ovarian failure), or a family history of fragile X syndrome, or intellectual or developmental disabilities with undetermined causes
• You are planning a pregnancy (preconception) or when you are pregnant, especially if you have had fertility problems and a family history of fragile X syndrome, or relatives with intellectual or developmental disabilities and the causes have not been identified
• You are a known carrier of a fragile X premutation or full mutation and are pregnant; you may choose to have your fetus tested.

It is recommended that anyone seeking or receiving fragile X testing do so in consultation with a genetic counselor or other genetic health professional to fully understand the implications of the results.

The laboratory report typically includes an interpretation of results.

For most women, two repeat sizes are reported because they have two X chromosomes. For most men, one repeat size is reported because they have one X chromosome and one Y chromosome. There are four possible ranges for repeat size, depending on the number of CGG triplet repeats:

Normal: 5 to 44 CGG repeats

• Not affected by fragile X syndrome or FMR1-related condition
• Not a carrier and not at risk of having a child with fragile X syndrome or related condition

Intermediate: 45 to 54 CGG repeats

• Not affected by fragile X syndrome or an FMR1-related condition
• A female with a repeat expansion in the intermediate range has a higher chance of passing a larger triplet expansion (a premutation – see below) to her children.
• The CGG repeat may expand and lead to fragile X syndrome after multiple generations, but it will not expand to a full fragile X mutation in one generation.

Premutation: 55 to about 200 CGG repeats

• Some women are at risk for fragile X-associated premature ovarian insufficiency (FXPOI).
• About 17% of women and 47% of men older than age 50 with a premutation are at risk for fragile X tremor/ataxia syndrome (FXTAS).
• With each pregnancy, women who are fragile X premutation carriers have a 50% chance of passing the X chromosome with the expanded FMR1 gene to their child. When this happens, there is a chance that the number of repeats will grow larger (expand) and surpass 200 when it is passed on, leading to the full mutation and fragile X syndrome. The chance that the premutation will expand to the full mutation range when it is passed on depends on its starting size. Premutations with more than 90 repeats almost always expand to full fragile X syndrome in the next generation.
• Fathers pass on either an X chromosome or a Y chromosome to their children. Fathers with an FMR1 premutation on their X chromosome will pass it to all their daughters. The premutation is not likely to expand when passed on by fathers. Since Y chromosomes do not have the FMR1 gene, fathers do not pass a premutation to their sons.

Full mutation: Usually more than 200 CGG repeats

• All males with a full mutation are affected with fragile X syndrome to some degree.
• Females with a full mutation can experience a wide range of signs and symptoms, and they can vary in severity.
• Even if fragile X syndrome is diagnosed prenatally in a fetus, it is impossible to predict which symptoms a child will have, or their severity.
• With each pregnancy, a mother with a full mutation has a 50% chance of passing it to her child.
• Men with full mutations and a diagnosis of fragile X syndrome do not commonly have children. If they do have children, fathers do not pass a full mutation to their sons since Y chromosomes do not have the FMR1 gene. It appears that fathers cannot pass on full mutations to their daughters, but scientists don't know why.

Signs and symptoms of fragile X syndrome can vary from person to person and evolve over time. Examples include:

• Impaired thinking (cognition), ranging from relatively mild learning disabilities to severe intellectual disability
• Development delays
• Delay in speech and language skills, especially in boys
• Attention deficit hyperactivity disorder (ADHD)
• Features of autism spectrum disorder (ASD) that affect communication and social interaction
• Behavioral issues related to ADHD or ASD include, for example, hand flapping, anxiety, sensitivity to touch, not making eye contact, difficulty paying attention, acting and speaking without thinking, and being very active.
• Anxiety, depression, aggression, obsessive compulsive disorder (OCD)
• Seizures
• Chronic ear infections
• Distinctive physical features, especially in males as they get older, including a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and enlarged testicles after puberty

Fragile X syndrome is the most common inherited intellectual disability in men and is a significant cause of intellectual disability in women. It occurs in approximately 1 in 4,000 men and 1 in 8,000 women. About half of people with fragile X syndrome also have autism spectrum disorder. Fragile X syndrome accounts for about 2 to 5 percent of all people with autism spectrum disorder.