Fragile X syndrome (FXS) Test

Overview

Fragile X syndrome (FXS) is a hereditary condition. FXS is caused by mutations in a gene known as the FMR1 gene when it was initially found. The FMR1 gene normally produces a protein known as FMRP. FMRP is required for proper brain development. People with FXS do not produce this protein. People with other fragile X-associated disorders have FMR1 gene mutations but normally produce some of the protein.

FXS affects both men and women. Females, on the other hand, frequently experience weaker symptoms than males. The actual number of persons affected with FXS is unknown, however a review of research studies estimated that around 1 in 7,000 males and 1 in 11,000 females had FXS.

Prenatal testing with chorionic villus sample or amniocentesis detects FMR1 mutations while the fetus is still in the womb and looks to be reliable.

Early detection of fragile X syndrome or carrier status is critical for providing early management in infants or fetuses with the syndrome, as well as genetic counselling regarding the possibility of a couple's future children being afflicted. Most parents observe delays in their children's speech and language abilities, difficulty in social and emotional domains, and increased sensitivity in particular situations.

How Is Fragile X Syndrome Inherited?

A mutation in the fragile X mental retardation (FMR1) gene causes fragile X syndrome. The FMR1 gene is found on chromosome X. This defective gene, which may be transmitted down through generations, is often acquired through the gene carried by women.

A fragile X carrier is someone who possesses a mutated FMR1 gene but no evident signs or symptoms of fragile X syndrome. Women who carry the fragile X gene have a 50% risk of conceiving a kid with fragile X syndrome. Fragile X carriers will transfer the mutated gene to all of their daughters but none of their boys. Daughters of carrier men are likely to be cognitively normal, but they are at risk of bearing children with fragile X syndrome.

The genetics of fragile X syndrome are complicated. Genetic counseling is recommended when someone has a family history of fragile X syndrome or is shown to be a carrier of fragile X.

Signs & Symptoms of Fragile X Syndrome

Signs that a child might have FXS include:

• Developmental delays (inability to sit, walk, or talk at the same time as other children of the same age).
• Learning impairments (difficulties learning new skills)
• Social and behavioral issues (such as not making eye contact, anxiety, trouble paying attention, hand flapping, acting and speaking without thinking, and being very active).
• FXS males often have some degree of intellectual handicap, which can range from mild to severe. Females with FXS may have normal IQ or a mild intellectual handicap. Autism spectrum disorder (ASD) is also more common in patients with FXS.

Who Should Have Fragile X Testing?

Fragile X testing should be considered in three broad circumstances:

• Clinical signs of Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome (FXTAS), or Fragile X-associated primary ovarian insufficiency (FXPAI) (FXPOI).
• Infertility or a family history of FXS, FXTAS, intellectual or learning difficulties, or autism of unknown etiology.
• Fragile X genetics and heredity can be traced back to a family or personal history of the disorder (i.e., carrier).

Specific indications for testing include:

• Any man or female with intellectual difficulties, developmental delays, speech and language delays, autism, or learning problems caused by an unknown factor.
• Infertility, increased FSH (follicle-stimulating hormone) levels, premature ovarian failure, primary ovarian insufficiency, or irregular menstruation are all symptoms of PCOS.
• Any adult over the age of 50 who has FXTAS symptoms such as intention tremors, ataxia, memory loss, cognitive impairment, or personality change, especially if they have a positive family history of Fragile X.
• Any woman who is planning a pregnancy or who displays an interest in or seeks Fragile X carrier testing.

Who Can Be a Fragile X Carrier?

Fragile X syndrome may affect anyone. It can be present in people of various ethnicities and races. One in every 250 women in the general population is a carrier of the faulty gene that causes fragile X syndrome. A woman of any age, whether or not she has previously had children, can have a kid with fragile X syndrome.

Risks For Fragile X Carrier

You are at greater risk if you have:

• There is a family history of fragile X syndrome.
• A family history of mental impairment, developmental delay, or autism caused by an unknown factor.
• Infertility issues caused by high follicle stimulating hormone (FSH) levels or early ovarian failure (POF).
• A history of adult-onset ataxia and/or tremors in the family.

Fragile X Carrier Test & Results?

The fragile X carrier test determines whether or not an individual is a fragile X carrier and their chances of producing a kid with fragile X syndrome. The test is carried out on a little amount of blood. Results are generally available within two weeks. More than 99 percent of the time, testing produces reliable results. This test does not detect other causes of mental retardation.

The possible results from a fragile X carrier test as showed below:

There are four possible results from a fragile X carrier test:

1. Negative: You are not a carrier of the most common FMR1 gene mutation, and your baby is not at risk for fragile X syndrome.
2. Intermediate: Your findings are in the negative to premutation range. Your infant is not at a higher risk of developing fragile X syndrome. Future generations might be at danger of developing fragile X syndrome.
3. Premutation: You are a carrier of a mutated FMR1 gene. You might be on the verge of menopause. Your child is at risk of developing fragile X syndrome. There is prenatal diagnostic testing available.
4. Complete mutagenesis: You are a carrier of a mutated FMR1 gene. Your child is at risk of developing fragile X syndrome. There is prenatal diagnostic testing available.

Genetic counseling is recommended and available when someone is shown to be a carrier of fragile X.

Genetic Testing for Fragile X syndrome

Genetic testing is a clinical diagnostic procedure that is frequently used to determine the root cause of a child's developmental delays, autism, or intellectual handicap.

Looking at the X chromosome under a microscope was the first diagnostic genetic test for Fragile X syndrome (FXS). It was discovered in the 1970s that some individuals with hereditary intellectual handicap had an X chromosome that was "fragile," as if the end had broken off. This is where the term "Fragile X" came from. This testing was quite accurate in identifying males with Fragile X syndrome, but it could not consistently identify females with the disorder or premutation carriers.

Genetic testing technology improved in the 1990s, and the particular gene associated with Fragile X syndrome — FMR1 — was found. Since then, very reliable Fragile X DNA testing has been widely available to identify people with various forms of repeat expansions inside the FMR1 gene.

Recommended genetic testing includes:

1. Chromosomal microarray analysis, which looks for extra or missing pieces of -genetic material.
2. Exome sequencing, which reads through part of a person’s genetic code.
3. A specific DNA test for Fragile X syndrome.

Currently, Fragile X testing must be ordered as a separate test since expansions of the FMR1 gene cannot be detected through microarray or exome sequencing.

Two main testing techniques are used when diagnosing Fragile X-associated disorders:

1. Polymerase chain reaction (PCR): This approach can determine the amount of the FMR1 gene's repetitive portion, including CGG repeat counts in the normal, intermediate, premutation, and complete mutation ranges.
2. Southern blot analysis: For complete mutations, laboratories often do a Southern blot study to check whether the gene is methylated, a chemical alteration that stops it from making its usual protein, FMRP.

AGG disruption testing can be done alone or as part of carrier testing. AGG analysis is usually performed as a follow-up test when a premutation or intermediate result is discovered in a woman carrier who wishes to have children.

The amount of CGG repeats inside the FMR1 gene is commonly reported by laboratories. They also give the methylation status and the existence of mosaicism if it is discovered for complete mutations. Because Fragile X testing is readily available through a variety of facilities, not all lab reports appear the same. Furthermore, many primary care physicians and non-genetics experts are uncomfortable with interpreting Fragile X test results.

Given the complexities of Fragile X inheritance, it is critical that families living with Fragile X-related diseases consult with a genetic counselor or geneticist to discuss the implications of a positive test report for the person and his or her extended family.

The Fragile X Test and Lab Report

• Is prenatal testing available?

Amniocentesis at 16 to 20 weeks or chorionic villus sampling (CVS) at 10 to 13 weeks can be used to identify if a fetus has inherited the fragile X gene.

• What’s the name of the test I should ask for?

Each laboratory may label the test differently, but the description will usually relate to "Fragile X CGG repeat analysis" or "Fragile X DNA test." This test is used to identify Fragile X syndrome and to see if a person (male or female) is a premutation carrier, which is used to determine FXPOI (Fragile X-associated primary ovarian insufficiency) and FXTAS (Fragile X-associated tremor/ataxia syndrome).

The test name may include the phrase "PCR with reflex to Southern blot," which means that if a complete mutation is discovered by PCR (polymerase chain reaction), the methylation status will be examined automatically using a Southern blot.

Fragile X DNA testing orders typically contain a CPT number, which is a billing procedure code. The current CPT code for Fragile X testing is 81243, with some laboratories incorporating 81244. If a healthcare professional is confused how to get a Fragile X DNA test, they can call the lab's customer service number.

• What’s included in a Fragile X laboratory report?

If a full mutation is detected, the majority of clinical laboratories report the CGG repeat number as well as the methylation status. If mosaicism is present, labs will also indicate it.

• What about AGG numbers, mosaicism, methylation, and FMR1 protein levels?

When testing to determine the cause of developmental delays, the number of AGG interruptions has no effect on a person's Fragile X syndrome symptoms and is not routinely analyzed or reported. It is occasionally reported on persons who have the premutation. Families should review the test findings with a genetic counselor and ask questions about any information not found on the report at that time.

Because this information is not currently relevant for medical care, clinical laboratories do not offer tests to evaluate Fragile X protein (FMRP) levels. Ask your genetic counselor or another trained healthcare expert to evaluate the lab data with you if you have particular questions.

Fragile X Testing Cost

The cost of Fragile X DNA testing might range from less than $100 to more than $1000. (U.S. dollars).

Insurance coverage and out-of-pocket costs for genetic testing are influenced by a variety of circumstances. Many people in the United States who have Medicaid as their primary or supplementary insurance may not have to pay any out-of-pocket expenses. For individuals who have private insurance, coverage varies based on the provider, and the cost of a family is determined by a variety of factors.

While some insurers may not cover genetic testing, most do under specific conditions, such as the diagnostic examination of a kid with developmental delay. Whether genetic testing is an approved benefit, families may still be responsible for certain expenditures, depending on whether their deductible has been reached or if their coverage includes a co-pay or co-insurance.

The ordering healthcare professional or the genetic testing facility may have office employees that may assist families in estimating their expected out-of-pocket cost for Fragile X testing.

What Do My Test Results Mean?

You are not at risk of having a kid with Fragile X syndrome if your findings are within the normal (i.e., typical) range.

If your result is intermediate (i.e., in the "gray zone"), you are not at risk of having a kid with Fragile X syndrome. However, the CGG repeat may grow to the premutation range in future generations of your family.

If you have a premutation and are male, all of your daughters will have the premutation. Your boys will inherit your Y chromosome but will not be carriers of the premutation. You might be at risk of developing FXTAS.

If you have a premutation and are female, you are more likely to have a kid with FXS, as well as infertility and early menopause (FXPOI) and, to a lesser extent, FXTAS.

If you have a complete mutation and are female, you may experience physical or learning difficulties as a result of Fragile X syndrome. You also have a chance of having a kid with Fragile X syndrome.

If your kid has a complete mutation, he will most likely have some level of intellectual handicap, such as language or behavioural disorders that would require professional assistance, such as special education.

If your daughter has a complete mutation, she is at risk for Fragile X syndrome, although she may just have moderate or no symptoms.

Conclusion

Fragile X syndrome (FXS) is the most frequent known genetic cause of mental impairment. It produces a wide variety of developmental and behavioral disorders, ranging from moderate anxiety or social interactional difficulties in people with normal intellectual functioning to more severe behavioral and cognitive deficiencies, including all degrees of mental retardation. FXS is also connected with connective tissue abnormalities, which contribute to some of the medical issues.

FXS can be identified with a blood test that analyzes a person's DNA. The test can be ordered by a doctor or genetic counselor. Changes in the FMR1 gene can potentially lead to fragile X-associated disorders, which can be tested for.

A FXS diagnosis might be beneficial to a family since it can give an explanation for a child's intellectual difficulties and behavioral issues. This enables the family and other caregivers to have a better understanding of the disease and manage care so that the kid can realize his or her full potential. However, the findings of DNA tests can have an impact on other family members and raise a variety of difficulties. As a result, anybody considering FXS testing should get genetic counseling before proceeding.