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Fragile X (FMR1)-Associated Disorders. ARUP Consult®. Retrieved December 19, 2024, https://arupconsult.com/content/fragile-x-fmr1-associated-disorders

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Fragile X (FMR1)-Associated Disorders

Last Literature Review: May 2024 Last Update:

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Pathogenic FMR1 variants are associated with multiple disorders, including fragile X syndrome (FXS), the most common heritable form of intellectual disability (ID); fragile X-associated primary ovarian insufficiency (FXPOI); fragile X-associated tremor ataxia syndrome (FXTAS); and fragile X-associated neuropsychiatric disorders (FXANDs). , 

Of those with FMR1 full mutations, all male individuals and approximately 50% of female individuals are expected to have FXS.  Male individuals with FXS may have autism spectrum disorder (ASD), connective tissue anomalies, and moderate ID, and may exhibit hyperactivity, perseverative speech, poor eye contact, social anxiety, and hand flapping or biting. ,  FXS in female individuals varies in presentation; some individuals will be asymptomatic, whereas others will demonstrate clinical features similar to those seen in male individuals. 

FXTAS is characterized by intention tremor and progressive ataxia, typically after the fifth decade of life.  Behavioral features and cognitive impairment may also develop.  Approximately 40% of male individuals and 16-20% of female individuals with an FMR1 premutation will develop FXTAS after 50 years of age ; rate is influenced by age and expanded repeat length.
 
FXPOI is characterized by primary ovarian insufficiency or hypergonadotropic hypogonadism before 40 years of age and is associated with FMR1 premutations.  Approximately 20% of female individuals with an FMR1 premutation may develop FXPOI. 

Symptoms of FXANDs may include addictive behavior, adult attention-deficit/hyperactivity disorder (ADHD), anxiety, or depression.  Both male and female individuals with FMR1 premutations are at risk for FXANDs. 

Molecular genetic testing for FMR1 mutations and premutations is used in diagnosis (including prenatal diagnosis) and carrier screening ,  for these conditions. Laboratory testing techniques may include methylation-specific and triplet repeat-primed polymerase chain reaction (PCR) or Southern blot. , 

Quick Answers for Clinicians

Which sample types are appropriate for prenatal fragile X testing?

Although either amniocentesis or chorionic villus samples can be tested for FMR1 mutations, methylation patterns are not fully established in the first trimester of pregnancy. ,  If chorionic villus sampling is used, follow-up amniocentesis may be required if an expanded allele is detected. ,  Therefore, it may be preferable to use amniocentesis for prenatal FMR1 testing. 

How does mosaicism affect testing for fragile X-associated disorders?

Mosaicism of FMR1 CGG triplet repeats is common.  Repeat size mosaicism refers to the presence of an expanded allele with subpopulations of cells demonstrating an unmethylated premutation and methylated full mutation.  Methylation mosaicism describes an FMR1 allele in the full-mutation size range that has varying degrees of methylation.  When mosaicism is present, there may be tissue-specific differences.  Male individuals with either repeat size or methylation mosaicism typically have intellectual disability (ID) but may be higher functioning than those with full mutations.  Female individuals with FMR1 repeat expansion mosaicism have highly variable phenotypes. 

How are fragile X syndrome-causing FMR1 variants other than CGG triplet repeat expansion detected?

Although more than 99% of fragile X syndrome (FXS) cases are associated with CGG triplet repeat expansion, other pathogenic variants (eg, deletions, single-nucleotide variants, and splicing variants) have been identified.  These variants can be detected using whole exome sequencing, whole genome sequencing, or Sanger sequencing.  There is some evidence for rare pathogenic intragenic variants, but the American College of Medical Genetics and Genomics (ACMG) does not provide guidance on their detection. 

Indications for Testing

Diagnostic FMR1 repeat expansion molecular testing is recommended for:

  • Individuals with unexplained ID or developmental delay (DD) , 
  • Male individuals with unexplained ASD; female individuals with unexplained ASD and additional finding(s) associated with FMR1-associated disorders , 
  • Individuals with findings consistent with FXTAS, including late-onset (after 50 years of age) cerebellar ataxia, intention tremor, dementia with other consistent findings, and/or multiple system atrophy (cerebellar subtype) , 
  • Female individuals with findings consistent with FXPOI, including primary ovarian insufficiency or infertility associated with elevated follicle-stimulating hormone (FSH) concentrations before 40 years of age , 
  • At-risk family members of individuals with FMR1 full mutations or premutations 
  • Individuals who were diagnosed with FXS through means other than molecular genetic testing 

Carrier screening for FMR1 variants should be offered to:

  • Female individuals who are pregnant or considering pregnancy and have a family history of fragile X-associated disorders or ID consistent with FXS 
  • Female individuals with elevated FSH before 40 years of age, unexplained ovarian failure, or unexplained ovarian insufficiency 

Prenatal diagnostic testing for FXS:

  • Should be offered to any known carrier of the FMR1 premutation or full mutation who is pregnant 
  • May include preimplantation genetic diagnosis in oocytes, although it may be challenging to retrieve oocytes, test for the CGG repeat expansion, and differentiate FMR1 alleles 

Population screening for FXS is not currently recommended. 

Pre- and posttest genetic counseling is recommended for all molecular genetic FMR1 testing. 

FMR1 Structure-Function Relationships

FMR1-associated disorders are caused by loss of function of a protein coded for by the FMR1 gene. , ,  More than 99% of cases are due to expansion of the FMR1 gene CGG repeat, although other pathogenic variant types do occur.  Transmission is X-linked.  The risk of transmitting fragile X-associated disorders is variable because the FMR1 CGG repeat expansion sequence is unstable and may change during oogenesis or postzygotic mitosis. , 

FMR1 Structure-Function Relationships
Allele SizeNumber of CGG RepeatsMethylationTransmissionClinical ImplicationsCarrier Status
Normal≤44UnmethylatedStableNot affected with an FMR1-associated disorderNot a carrier
Intermediate (also referred to as borderline, gray zone)45-54UnmethylatedUnstable, but not reported to expand to a full mutation in 1 generationNot affected with an FMR1-associated disorderNot a carrier
Premutation55-200Unmethylated

Female individuals: stability influenced by number of CGG repeats and AGG interruptionsa

Male individuals: stable

Female individuals: at risk for FXPOI, FXTAS, and FXANDs

Male individuals: at risk for FXTAS and FXANDs

Carrier

Female individuals: may pass premutation or full mutation to offspring

Male individuals: will pass premutation to all female offspring and no male offspring

Full mutation>200MethylatedUnstable; somatic variation present

Female individuals: may be affected with FXS but severity variesb; not at risk for FXPOI, FXTAS, or FXANDs

Male individuals: affected with FXS; not at risk for FXTAS or FXANDs

Female individuals: 50% chance of passing full mutation to offspring

aThe stability of premutations may be influenced by the number of CGG repeats and AGG interspersions within the CGG repeat sequence.

bThe size of the CGG repeat and degree of associated methylation cannot be used to predict the presence or severity of symptoms.

Sources: Spector, 2021 ; Hunter, 2019 ; Finucane, 2012 

Mosaicism may present a challenge in the diagnosis of FMR1-associated disorders. Mosaicism for both CGG repeat size and methylation may occur and may impact disease severity. 

Interruptions of AGG are present every 9-10 repeats within the CGG repeat sequence in normal FMR1 alleles and contribute to allele stability.  Premutations with uninterrupted CGG repeats are more likely to expand upon transmission.  Therefore, assessing for AGG interruption structure may provide useful information for genetic counseling, especially for female individuals with premutations. 

Molecular Genetic Methods in FMR1 Testing

Although cytogenetic testing was historically used to assess for FXS, it is no longer an acceptable technique for the evaluation of fragile X-associated disorders. ,  Molecular genetic analysis is preferred for FMR1 testing.  Because no single molecular genetic testing method provides all relevant information about FMR1 variants, multiple methods are often used to assess allele size and methylation status.  Triplet repeat-primed PCR and methylation-specific PCR are commonly used testing methods.

ARUP Laboratory Tests

2014314
Autism and Intellectual Disability Comprehensive Panel 2014314
Method

Tandem Mass Spectrometry/Electrophoresis/Spectrophotometry/ Gas Chromatography-Mass Spectrometry/Liquid Chromatography-Tandem Mass Spectrometry/Quantitative Liquid Chromatography-Tandem Mass Spectrometry, Genomic Microarray (Oligo-SNP Array), Polymerase Chain Reaction/Capillary Electrophoresis

References

  1. GeneReviews - FMR1 Disorders

    Hunter JE, Berry-Kravis E, Hipp H, et al. FMR1 disorders. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update Nov 2019; accessed Apr 2024.