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Fragile X Carrier Screening

What is Fragile X Syndrome?

Fragile X syndrome is the most common cause of inherited intellectual disability, affecting approximately one in 3,600 males and one in 4,000-6,000 females.1 It can occur in any ethnic group. Intellectual disability may range from learning disabilities to severe mental retardation and autism. Physical characteristics are often more pronounced in adult males and may include macrocephaly, enlarged ears, and a long face with a prominent chin. Approximately 50% of females with a full mutation have borderline or mild intellectual disability.2

Fragile X syndrome is caused (in >99% of cases) by an expansion of an unstable CGG repeat in the FMR1 gene. Most individuals have a CGG repeat size between 5-44 repeats, which is considered normal. Those with fragile X syndrome have a repeat size greater than 200, which is referred to as a full mutation.3

An estimated one in 259 females and one in 755 males in the general population have an FMR1 premutation with 55 to 200 CGG repeats.4 Fragile X premutation carriers do not experience intellectual disability, but they may be affected by other symptoms. Approximately 21% of female premutation carriers experience premature ovarian insufficiency. Approximately 40% of male and 8-17% of female premutation carriers over the age of 50 report experiencing symptoms of Fragile X-associated tremor/ataxia syndrome (FXTAS).5,6 FXTAS is a neurodegenerative disorder characterized by cerebellar ataxia, intention tremor, progressive cognitive decline, and psychiatric disorders.

How is Fragile X Syndrome Inherited?

Fragile X syndrome is inherited in an X-linked manner. Female premutation carriers are at risk to have children with Fragile X syndrome. If a female premutation carrier passes the X chromosome with the premutation to a child, it may remain stable or it may expand, possibly to a full mutation. The risk of expansion depends in part on the number of maternal CGG repeats and the presence of interspersed AGG repeats. The smallest premutation that has been reported to expand to a full mutation in one generation is 56 repeats.7,8

Reporting of Fragile X Testing Results:

Carrier StatusNumber of Triplet RepeatsHow this affects the motherRisk to the pregnancy for Fragile X syndrome
Normal5-44The mother is not a carrier for Fragile X.The pregnancy is not at risk for Fragile X syndrome.
Intermediate/
Grey zone
45-54The mother is not a carrier for Fragile X. Offspring and future generations may carry a premutation.The pregnancy is not at risk for Fragile X syndrome; however, future generations may be at risk for Fragile X syndrome. Genetic counseling is recommended.
Premutation55-199The mother is a carrier for Fragile X. She has a potential risk of early ovarian failure and is at risk to develop FXTAS.The pregnancy is at risk for Fragile X syndrome. Genetic counseling is recommended, and prenatal genetic diagnostic testing should be offered.
Full mutation200 or moreThe mother has a full mutation of Fragile X, which can produce variable symptoms in females.There is a 50% chance to pass on the full mutation to a child. Genetic counseling is recommended, and prenatal genetic diagnostic testing should be offered.

Who Should be Offered Fragile X Carrier Testing?

According to ACOG Committee Opinion Number 469, carrier testing for Fragile X may be offered for women with a family history of:

  • Fragile X-related disorders
  • Unexplained mental retardation or developmental delay
  • Autism
  • Premature ovarian insufficiency (or elevated FSH <40 yrs)

Women who request Fragile X carrier screening, regardless of family history, should be offered screening after genetic counseling on the risks, benefits, and limitations of screening.

Is there Prenatal Diagnosis for Fragile X Syndrome?

Yes. Prenatal testing by chorionic villi sampling or amniocentesis can be performed to determine whether or not a fetus is affected with Fragile X syndrome.

References

  1. National Fragile X Foundation. Prevalence. Fragile X Syndrome. https://fragilex.org/understanding-fragile-x/fragile-x-101/prevalence/. Accessed September 10, 2019.
  2. National Fragile X Foundation. Prevalence. Born with the full mutation for Fragile X, worldwide. https://fragilex.org/understanding-fragile-x/fragile-x-101/prevalence/. Accessed September 10, 2019.
  3. National Organization for Rare Disorders. Fragile X Syndrome. General Discussions. https://rarediseases.org/rare-diseases/fragile-x-syndrome/. Accessed September 10, 2019.
  4. McConkie-Rosell A et al. Genetic counseling for fragile x syndrome: updated recommendations of the national society of genetic counselors. Journal Of Genetic Counseling. 2005 14(4):249-70.16047089.
  5. Pirozzi F et al. The FRAXopathies: definition, overview, and update. American Journal Of Medical Genetics. Part A. 2011 155A(8):1803-16.21739597.
  6. Jacquemont S et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. Jama : The Journal Of The American Medical Association. 2004 291(4):460-9.14747503.
  7. Fernandez-Carvajal I et al. Expansion of an FMR1 grey-zone allele to a full mutation in two generations. The Journal Of Molecular Diagnostics : Jmd. 2009 11(4):306-10.19525339. (PMID: 19525339).
  8. Spector and Kronquist (2006) Technical Standards and Guidelines for Fragile X Testing: Supplement to Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics. Online: http://www.acmg.net/Pages/ACMG_Activities/stds-2002/stdsmenu-n.htm Accessed July 2011.