Fragile X Syndrome Testing & Diagnosis
During the 1970s and 1980s the only available tool for diagnosing Fragile X syndrome (FXS) was the chromosome (i.e., cytogenetic) test. While it was helpful, it was not always accurate. In the 1990s, scientists identified the FMR1 gene that causes FXS and accurate DNA testing became available.
The FMR1 DNA test (sometimes called the Fragile X DNA test) thus replaced chromosome testing and became the standard of care for determining the presence of Fragile X. DNA testing detects more than 99% of individuals (both males and females) with FXS, as well as Fragile X carriers.
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Who Should Have Fragile X Testing?
There are three general circumstances in which Fragile X testing should be considered:
- Clinical symptoms that suggest Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome (FXTAS), or Fragile X-associated primary ovarian insufficiency (FXPOI).
- A family history of FXS, FXTAS, intellectual or learning disabilities or autism of unknown cause, or infertility.
- Family or personal history of a Fragile X genetics and inheritance (i.e., carrier).
Specific indications for testing include:
- Any male or female with intellectual disabilities, developmental delay, speech and language delay, autism, or learning disabilities of unknown cause.
- Any female with infertility, elevated FSH (follicle-stimulating hormone) levels, premature ovarian failure, primary ovarian insufficiency, or irregular menses.
- Any adult over 50 with features of FXTAS, including intention tremors, ataxia, memory loss, cognitive decline, or personality change, especially in combination with a positive family history of Fragile X.
- Any preconception or pregnant woman who expresses interest in or requests Fragile X carrier testing.
Lab Tests for Fragile X
The FMR1 DNA test can be administered with two different lab procedures:
- The Southern blot analysis test determines if the gene has a full mutation, its approximate size, whether the gene has been “methylated,” and if there is mosaicism of the gene (a mixture of different cell types).
- The polymerase chain reaction (PCR) analysis can determine the actual number of CGG repeats (a pattern of DNA) that are present in the Fragile X gene. For various technical reasons, PCR has not been the test of choice to diagnose a full mutation, but is quite accurate in determining premutation and normal gene repeat numbers. However, PCR is less expensive and quicker than Southern blot, and recent advances in technology have increased its ability to identify Fragile X full mutations. PCR may thus be the only test used in the near future.
Testing Cost and Reporting Time
The blood test usually ranges from $300 to $600, and results are usually available in two to four weeks.
What do test results report? The test will determine the number of CGG repeats that are present in the area of the Fragile X gene that is studied. If Southern blot is ordered, the test will also tell you the methylation pattern of the Fragile X gene. If the testing is performed on a female, two numbers will be provided—one for each X chromosome. In males, only one result will be provided, though that number might be a range, such as 200–400, because the gene often expands in an unpredictable manner.
Who receives the test results? Test results go to the provider who ordered the test, such as the genetic counselor or physician. Other recipients may include a pediatrician, obstetrician, or other health care provider involved in the patient’s or family’s care.
How are testing arrangements made? The test must be ordered by a genetic counselor or physician. A genetic counselor often will facilitate the testing, and make certain that the correct drawing, shipping, and processing of the sample occurs. The genetic counselor is trained and experienced in the interpretation and explaining of the test results. They can coordinate any follow-up appointments and work with your physician to make referrals to resources in your area.
In most cases you will be directed to go to a blood drawing station for a blood drawing procedure. Although this facility is often referred to as a lab, it is not the actual lab doing the DNA test. After the blood is drawn it is sent to a specific genetics or “reference” lab for the genetic test.
If your insurance company (or state/public insurance such as Medicaid) is paying for the testing, it is likely that the sample will go to the laboratory with which they are contracted. If you are paying for the test yourself, your physician or genetic counselor can locate a genetics lab in your area or one with which they have a relationship. The National Fragile X Foundation can assist your provider in locating a laboratory as well.
CPT and ICD-10 Codes for Fragile X Testing
CPT—current procedural terminology—codes are standardized classifications for services provided, and are mostly used by insurance companies. CPT codes most commonly associated with FMR1 DNA testing:
- 81243 — FMR1 gene analysis, evaluation to detect abnormal alleles
- 81244 — FMR1 gene analysis, characterization of alleles (if appropriate)
ICD—or international classification of disease—codes are the diagnostic classification standard for all clinical and research purposes (overseen by the World Health Organization). ICD-10 codes for FXS:
- Q99.2— Fragile X syndrome
- Z31.440 — Encounter of male for testing for genetic disease carrier status for procreative management
- Z31.430 — Encounter of female for testing for genetic disease carrier status for procreative management
Other Tests for Children with Developmental Delay
Physicians and other providers ordering Fragile X testing often arrange for additional genetic testing to provide more information on a child’s condition. Depending on the child’s presenting features or symptoms, this might include chromosome analysis; CMA (chromosomal microarray analysis), also known as CGH (comparative genomic hybridization); FISH (fluorescence in situ hybridization) testing for other single gene conditions such as VCFS (velocardiofacial syndrome), and metabolic/biochemical tests. Other types of medical evaluations might be recommended as well, including an MRI, EEG (a test that measures brain waves), CT scan, or X-ray.
Chromosomal Microarray Analysis and the DNA Test for Fragile X
Chromosomal microarray analysis is a powerful test for detecting certain genetic causes of developmental disabilities; however, it is not able to detect Fragile X mutations of any kind.
For this reason, the diagnostic work-up of children with autism, global developmental delay, or intellectual disabilities should include both a chromosomal microarray analysis and a separate Fragile X DNA analysis. If your child has only the microarray analysis but not the specific DNA test for Fragile X, then they have not been checked for Fragile X.
Autism Genetic Testing Panels
Because there are genes known to be associated with autism—Fragile X being the most common—it is important to test for the presence of an underlying genetic disorder. Autism genetic testing panels are marketed for an autism spectrum disorder diagnosis of unknown causes, but note that not all include testing for Fragile X. To learn more, including labs and tests that include the FMR1 gene, see After the Autism Diagnosis: What You Need to Know About Genetic Testing.
Fragile X Genetics & Inheritance »
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.
Fragile X Syndrome & Autism »
When associated with FXS, autism is caused by the genetic change or mutation in the Fragile X gene—the most common genetic cause of autism.
A Blood Test for Autism? Not so Fast »
The notion that autism itself can be directly diagnosed through a blood test is incorrect and misleading.
Fragile X Syndrome Testing & Diagnosis »
DNA testing detects more than 99% of individuals (both males and females) with FXS, as well as Fragile X carriers.
The Who, What & How for Genetic Counseling »
Who should seek counseling? What does a genetic counselor do? How do I find one?