Fragile X-Associated Disorders

Fragile X-associated disorders (FXD) is a group of genetic conditions caused by changes in the FMR1 gene and include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). FXD can affect people in a variety of ways, causing intellectual disabilities, autism spectrum disorders, behavioral changes, imbalance, tremor, memory problems, and decreased ovarian function.

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Fragile X-associated disorders (FXD) is a group of genetic conditions caused by changes in the FMR1 gene and include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). FXD can affect people in a variety of ways, causing intellectual disabilities, autism spectrum disorders, behavioral changes, imbalance, tremor, memory problems, and decreased ovarian function.

Approximately 1 in every 150 women and 1 in every 470 men in the United States carries a change in the FMR1 gene that can impact both health and behavior.1 Ambry offers comprehensive FMR1 repeat analysis and methylation testing to assist in providing a molecular diagnosis, which can inform appropriate treatment recommendations for individuals affected with fragile X-associated disorders (FXD).

 

Disease Name 
Fragile X Syndrome
Fragile X-associated Tremor/Ataxia Syndrome
Fragile X-associated Primary Ovarian Insufficiency
X-Linked Intellectual Disability
Disease Information 

Fragile X Syndrome
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability, affecting approximately 1/3,600 males and 1/4,000 females in the United States.1 Individuals with FXS can exhibit autism spectrum disorders, behavioral changes and cognitive impairment. FXS is caused by mutations of the FMR1 gene, which is actively involved during embryogenesis and contributes to fetal brain and CNS development. 2,3 Molecular diagnosis involves locating an expansion of an unstable CGG trinucleotide repeat sequence within the promoter region of FMR1, which is located on the X chromosome. The presence of more than 200 CGG repeats in a row indicates a full mutation, most often leading to methylation of the gene and silencing of the gene product. Methylated full mutations lead to FXS.4

Fragile X-Associated Tremor/Ataxia Syndrome
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that can cause ataxia, intention tremors, memory loss, mood instability, and cognitive decline.5,6,7 FXTAS is more common in men than women, and can often be mistaken for Parkinson disease or Alzheimer disease. FXTAS is caused by the presence of an expansion of an unstable CGG trinucleotide repeat sequence within the promoter region of FMR1. Individuals with 55-200 CGG repeats carry a premutation of the FMR1 gene and are at risk for developing FXTAS. One-third (33%) of men with FMR1 premutations will develop symptoms of FXTAS.1,5,8 A smaller number of women with an FMR1 premutation will develop FXTAS, approximately 5-8%.1,5,8

Fragile X-associated Primary Ovarian Insufficiency
Fragile X-associated primary ovarian insufficiency (FXPOI) is a disorder that causes the ovaries to function at decreased capacity. Symptoms can include absent or irregular menses, signs of menopause such as hot flashes, premature menopause, and infertility9. FXPOI is caused by the presence of an expansion of an unstable CGG trinucleotide repeat sequence within the promoter region of FMR1, resulting in between 55-200 CGG repeats. 20-25% of women with FMR1 premutations will develop FXPOI.1,9

Testing Benefits & Indication 

Genetic testing is useful for diagnostic confirmation in symptomatic individuals and for testing of at-risk asymptomatic family members (including prenatal diagnosis). Molecular confirmation of a diagnosis may help avoid unnecessary testing and procedures, as well as guide recommendations for medical treatment and screening.

Per American Congress (formerly College) of Obstetrics and Gynecology and American College of Medical Genetics and Genomics guidelines,10,11 FMR1 testing should be considered for any of the following:

  • Any individual with intellectual disability, developmental delay, learning disabilities of unknown cause, and/or an autism spectrum disorder or autism-like characteristics 
  • Families with a history of FXS or intellectual disability due to unknown cause
  • Fetuses of mothers known to have an FMR1 premutation or full mutation, as well as for those with a family history of FXS or intellectual disability of unknown cause 
Test Description 

Fragile X DNA Analysis includes FMR1 CGG repeat detection by a triple primed polymerase chain reaction (PCR) using a standardized kit to selectively amplify the regions of gDNA corresponding to the FMR1 promoter gene followed by capillary electrophoresis for fragment size analysis. Methylation status using methylation sensitive PCR analysis (mPCR) is performed as a reflex test if PCR indicates a full mutation or a premutation (>53 repeats) allele.

Mutation Detection Rate 

Ambry’s testing analyzes the CGG repeat expansion in the FMR1 gene, which been associated with >99% of clinically affected individuals with a fragile X-associated disorder (FXD) (clinical and analytic sensitivities). A small portion (<1%) of FXD are due to rare mutations in areas of the FMR1 gene not evaluated by this test.

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above in the Quick Links section at the top of this page.

Special Note for Prenatal Samples: Ambry only accepts amniotic fluid cultures for prenatal fragile X syndrome testing.  Please call for more information.

Turnaround Time 
TEST CODE TEST NAME TURNAROUND TIME 
4544 Fragile X DNA Analysis
(FMR1 repeat analysis and FMR1 methylation analysis)          
7-14 days

 

Genes 
Techniques 
References 
  1. Seltzer M, et al. Prevalence of CGG expansions of the FMR1 gene in a US population-based sample. Am J Med Genet B. 2012;159B(5):589-97.
  2. Bear M, et al. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004;27:370-7.
  3. Abitbol M, et al. Nucleus basalis magnocellularis and hippocampus are the major sites of FMR1 expression in the human fetal brain. Nature Genet. 1993;4:147-153.
  4. Verkerk A, et al. Identification of a gene (FMR1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991;65:905-914.
  5. Berry-Kravis E, et al. Fragile X-Associated Tremor/Ataxia Syndrome: Clinical features, genetics, and testing guidelines. Movement Disorders. 2007;22(14):2018-2030.
  6. Grigsby J, et al. Impairment in the cognitive functioning of men with fragile X-associated tremor/ataxia syndrome (FXTAS). J of Neurol Sci. 2006;248: 227-233.
  7. Hessl D, et al. Amygdala dysfunction in men with the fragile X premutation. Brain. 2007;130:404-416.
  8. Hagerman P, et al. The fragile-X premutation: a maturing perspective. Am J Hum Genet. 2004;74:805-816.
  9. Sullivan SD, et al. FMR1 and the continuum of primary ovarian insufficiency. Semin Reprod Med. 2011;29(4):299-307.
  10. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 469: Carrier screening for fragile X syndrome. Obstet Gynecol. 2010 Oct;116(4):1008-10.
  11. Monaghan KG, et al. ACMG Standards and Guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics. Genet Med. 2013 Jul;15(7):575-86.