Fragile X Carrier

Numerous questions emerge when you or a family member are informed that you are a “carrier” of the fragile X gene mutation. Do you have a partial or full mutation of the FMR1 gene? What are the implications for your health, family, and future? The following information aims to clarify the distinction between individuals with a full mutation, or Fragile X syndrome (FXS), and a fragile X premutation and the associated health conditions and diagnostic tests available to help you detect this hereditary disorder.

Fragile X Syndrome

Fragile X syndrome (FXS) is a genetic disorder caused by the full mutation of the FMR1 gene located on the X chromosome. A mutation of the FMR1 gene can hinder the production of the fragile X RNA-binding protein (FMRP), resulting in intellectual disability, behavioral and learning difficulties, and other physical traits. Although FXS affects both genders, males are typically affected more frequently and with greater severity than females. Some females may not exhibit any of the behavioral, cognitive, or physical characteristics that are more prevalent in males. This is because males only have one X chromosome, whereas females have two X chromosomes, and one of their X chromosomes can offset the effects of the other mutated X chromosome. 1

Signs, symptoms, and severity of FXS may vary from person to person. The most common physical features of FXS may include large ears, a long face, soft skin, and flexible joints. Behavioral issues may include sensory processing challenges, Attention Deficit/Hyperactive Disorder (ADHD), anxiety disorders, social deficits, Autism Spectrum Disorders (ASD), and increased risk for aggression. Cognitive abilities in FXS range from mild learning disabilities to more severe intellectual disabilities. Other medical co-occurring conditions associated with FXS may include ear infections (often due to poor connective tissue), strabismus (crossed eyes), and seizures.1

A small number of females with the full mutation of the FMR1 gene, which causes FXS, will show no symptoms of the disorder, whether intellectual, behavioral, or physical. These females are frequently identified through genetic diagnosis only after another family member has been diagnosed.1

Fragile X Premutation Carriers

A carrier is an individual who possesses an abnormal gene that raises the likelihood of having a child or grandchild with a genetic disorder. The majority of gene mutations are “silent.” This implies that carriers of gene mutations can pass on their abnormal gene without showing any signs or symptoms of the disease themselves. This does not always hold true in Fragile X as some fragile X premutation carriers are susceptible to developing fragile X-associated disorders such as Fragile X-associated Tremor/Ataxia syndrome (FXTAS) and Fragile X-associated Primary Ovarian Insufficiency (FXPOI). Only genetic testing can reveal if you are a fragile x premutation carrier.2

Females with fragile X premutation have a 50% chance of passing it to their children. These children will either be carriers of the mutated gene or have FXS. Males who carry the fragile X premutation will only pass it to their daughters but never their sons. The daughters will become carriers in this situation but will not develop FXS.3 4

In addition to FXTAS and FXPOI, fragile X carriers may also be at an increased risk for depression, anxiety, mood disorders, sleep apnea, respiratory and gastrointestinal difficulties, autoimmune disorders, neuropathy, and bone fractures.4

Fragile X-associated Tremor/Ataxia syndrome (FXTAS)

Fragile X-associated Tremor/Ataxia syndrome is a neurodegenerative condition with “adult-onset” that typically affects male carriers over 50. Females comprise a small portion of the FXTAS population, and their symptoms are typically milder. FXTAS affects approximately 40% of males over 50 and 8% to 16% of females over 40 who are fragile X premutation carriers.5
The nature and severity of FXTAS symptoms vary from person to person. Some will experience several symptoms that increase swiftly, while others will experience fewer symptoms that remain mild for many years. The most common symptoms of FXTAS include:5

  • Intention tremor
  • Gait ataxias
  • Parkinsonism (resting tremors)
  • Cognitive decline
  • Neuropathy
  • Low blood pressure (orthostatic hypotension)
  • Mood instability and personality changes
  • Problems with executive function and decision-making
  • Difficulty learning new tasks
  • Autonomic dysfunction such as loss of bladder function

Females can experience the same neurological symptoms as males, but the severity is nearly always reduced. The majority of affected females exhibit tremors or ataxia. Psychiatric and mood disorders are likewise less common in females, however, they are more likely to experience anxiety and depression. Additional symptoms experenced by some females include:5

  • Fibromyalgia or generalized muscle pain
  • Thyroid disorders (usually hypothyroidism)
  • Seizure disorders

Fragile X-associated Primary Ovarian Insufficiency (FXPOI)

Fragile X-associated Primary Ovarian Insufficiency is a condition in which the ovaries of female carriers do not function at full capacity.6

FXPOI is characterized by absent or irregular cycles, “sub-fertility” or infertility, hot flashes, and on the more severe end of the spectrum, premature ovarian failure (POF), which is the cessation of menstruation before the age of 40. For premutation carriers, FXPOI causes menstrual cycle irregularities in around 3% of femalesduring their teens or twenties, with 1% stop menstruation before 18. Females with a premutation may also experience premature menopause between the ages of 40 and 45 (the natural age of menopause is between 45 and 55).6

Even though females with FXPOI may experience similar symptoms to those of menopause, such as hot flashes and vaginal dryness, FXPOI differs significantly from menopause in several significant respects. For example, females with FXPOI can still become pregnant because their ovaries may occasionally release viable eggs, unlike those who have reached menopause.6

Who Should Consider Testing for Fragile X?

In general, fragile X testing should be considered in these situations:7

  • Clinical signs of FXS, FXTAS, or FXPOI.
  • Family history of FXS, FXTAS, intellectual or learning disabilities, or infertility.
  • Any male or female with intellectual disability, developmental delay, speech and language delay, autism sprectrum disorder, cognitive decline or unknown source of learning problems.
  • Family history or personal history of a fragile X genetics and inheritance.
  • Any preconception or pregnant woman interested in or requesting carrier testing for fragile X.
  • 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.

Genetic Testing for Fragile X

The fragile X carrier test helps determine whether a person is a fragile X carrier and the likelihood of having a child with FXS. These tests provide accurate results 99% of the time.8 A blood test that analyzes a person’s DNA sample can diagnose FXS or determine whether the person is a carrier.

In contrast to most prenatal carrier testing, fragile X carrier status has significant reproductive and health implications for the tested individual and potential developmental impairment risks in future children. The American Congress of Obstetricians and Gynecologists (ACOG) recommends prenatal screening and genetic counseling for females with a family or personal history of fragile X, unexplained mental impairment or developmental delay, or premature ovarian insufficiency.9

Genetic testing procedures that are performed to identify fragile X-associated disorders include the following:7

  • Polymerase chain reaction (PCR) – This approach can identify the size of the repetitive part of the FMR1 gene, including the number of cytosine, guanine and guanine (CGG) repeats in the normal, intermediate, premutation, and full mutation ranges.
  • Southern blot analysis – For full mutations, laboratories often do a Southern blot analysis to determine whether or not the FMRI gene is methylated, meaning it has undergone a chemical alteration that prevents it from producing its typical protein, FMRP.

What Are the Possible Results of Genetic Testing?

Fragile X carrier screening checks a particular segment of the FMR1 gene, which is situated on the X chromosome. Repeating DNA sequences, representing the combination of the cytosine, guanine and guanine building blocks of the DNA and denoted by the letters CGG, are contained inside this specific region of the FMR1 gene. This DNA region is normally replicated five to 40 times in unaffectedd individuals. An “allele” is a term used to describe an individual’s gene. A fragile X carrier test can yield one of four outcomes:7 10

  • Negative or Normal Alleles – The individual is not a carrier of the mutated FMR1 gene. Any CGG repeat count less than 45 is considered a negative result.
  • Intermediate Alleles (gray zone) – The person is deemed to have an intermediate outcome if the CGG repeat count is between 45 and 55. People with intermediate results are not likely to have a child with FXS and are unlikely to experience any health concerns related to fragile x-associated disorders. However, for those with an intermediate amount of repeats, the potential exists that the FMR1 mutuation will evolve into a premutation over the next several generations.
  • Premutation Alleles – A premutation is a CGG repetition count between 55 and 200. A person with a premutation increases their chances of having a child with FXS. Furthermore, females with premutation are more likely to have FXPOI. Males and females who have a premutation are at risk of developing FXTAS.
  • Full Mutation – A person has a full fragile X mutation (FXS) if they have more than 200 CGG repeats. Males with a full mutation will likely experience many symtpoms of FXS, whereas females with a full mutation will generally exhibit fewer symptoms.

Because of the complexity of FXS and fragile-x associated disorders, affected families may wish to consult with a genetic counselor or geneticist, their healthcare provider, or a fragile X clinic to understand the implications of testingresults.

References

  1. National Fragile X Foundation, Fragile X 101. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/fragile-x-101/
  2. National Fragile X Foundation, Premutation Carriers. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/fragile-x-101/premutation-carriers/
  3. FRAXA Research Foundation, What Is Fragile X Syndrome? Retrieved Oct 17, 2022, from https://www.fraxa.org/fragile-x-syndrome/
  4. Eunice Kennedy Shriver National Institute of Child Health and Human Development. Science Update: Fragile X carriers may be at higher risk for several health conditions, NIH-funded study suggests. Retrieved Oct 17, 2022, from https://www.nichd.nih.gov/newsroom/news/082919-FMR1-premutation
  5. National Fragile X Foundation, Fragile X–Associated Tremor/Ataxia Syndrome | FXTAS. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/tremor-ataxia-syndrome-fxtas/
  6. National Fragile X Foundation, Fragile X-Associated Primary Ovarian Insufficiency| FXPOI. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/fxpoi-primary-ovarian-insufficiency/
  7. National Fragile X Foundation, Genetic Testing for Fragile X Syndrome and Associated Disorders. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/fragile-x-101/testing-diagnosis/
  8. University of California, San Francisco. Carrier Testing for Fragile X Syndrome. Retrieved Oct 17, 2022, from https://www.ucsfhealth.org/en/education/carrier-testing-for-fragile-x-syndrome
  9. Gutiérrez JF, Bajaj K, Klugman SD. Prenatal Screening for Fragile X: Carriers, Controversies, and Counseling. PMC3651542. Rev Obstet Gynecol. 2013; 6(1): e1–e7.
  10. National Fragile X Foundation, Genetics & Inheritance. Retrieved Oct 17, 2022, from https://fragilex.org/understanding-fragile-x/fragile-x-101/genetics-inheritance/

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