FMR1-Related Disorders

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General Information

Lab Name
FMR1-Related Disorders
Lab Code
FMR1
Epic Ordering
FMR1-Related Disorders
Description

Fragile X Syndrome (FXS)

FXS, the most common inherited cause of intellectual disability, affects about 1:4,000-6,250 individuals with one X chromosome (typically assigned male sex at birth); clinical features can include varying degrees of cognitive deficits, seizures, and certain characteristic physical issues. Individuals with two X chromosomes (typically assigned female sex at birth) exhibit symptoms at about half the prevalence as individuals with one X chromosome, and symptoms are generally milder in severity. In over 99% of cases, FXS is caused by a full repeat expansion (>200 CGG trinucleotide repeats) in the FMR1 gene.

Fragile X Tremor/Ataxia Syndrome (FXTAS)

FXTAS can occur in individuals with an FMR1 allele in the premutation range (55-200 CGG repeats) and is characterized primarily by intention tremor, cerebellar gait ataxia, and cognitive impairment. Onset of FXTAS is typically between age 60-65 years; for individuals with an FMR1 allele in the premutation range, FXTAS occurs in approximtely 40% of individuals with one X chromosome and 16-20% of individuals with two X chromosomes.

Fragile X-Related Primary Ovarian Insufficiency (FXPOI)

FXPOI can occur in individuals who have ovaries and an FMR1 allele in the premutation range (55-200 CGG repeats) and is characterized by primary ovarian insufficiency prior to the age of 40. FXPOI occurs in approximately 12-28% of individuals who have ovaries and an FMR1 allele in the premutation range.

Note: Individuals with two X chromosomes and an FMR1 allele with <100 CGG repeats could have additional testing to determine probability of allele expansion upon transmission. (see Lab Test Catalog, lab mnemonic [570] for more info).

The Fragile X DNA test performed is the same for FXS, FXTAS, or FXPOI.

Genetic Counseling

Genetic counseling for FMR1-related conditions is complex and challenging. Genetic counseling for patients and families undergoing or considering genetic testing is highly recommended. The laboratory can provide referrals to genetics clinics in the patient’s locale.

References
  • Hall DA and O'Keefe JA. Clinical neurogenetics: fragile x-associated tremor/ataxia syndrome. Neurol Clin 2013, 31:1073-84. 24176424
  • Hunter JE, Berry-Kravis E, Hipp H, et al. FMR1 Disorders. 1998 Jun 16 [Updated 2019 Nov 21]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1384/
  • Monaghan KG, Lyon E, Spector EB, and erican College of Medical Genetics and Genomics. 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, 15:575-86. 23765048
  • Pirozzi F, Tabolacci E, and Neri G. The FRAXopathies: definition, overview, and update. Am J Med Genet A 2011, 155A:1803-16. 21739597
  • Sullivan SD, Welt C, and Sherman S. FMR1 and the continuum of primary ovarian insufficiency. Semin Reprod Med 2011, 29:299-307. 21969264
Forms & Requisitions

Genetics Requisition

Synonyms
ataxia, autism, developmental delay, FMR1, Fragile X, Fragile X-associated tremor ataxia syndrome, FXTAS, intellectual disability, POF, POI, premature ovarian failure, primary ovarian insufficiency, tremor
Components

Interpretation

Method

Test performed using polymerase chain reaction (PCR) with capillary electrophoresis to detect expansions of the CGG trinucleotide tract in the 5’UTR of the FMR1 gene.

Note: There are rare FMR1 mutations; less than 1% of individuals affected with FXS do not have an FMR1 allele in the full expansion ("full mutation") range but carry a deletion or point mutation in the FMR1 gene. Pathogenic variants other than the typical CGG repeat expansion (e.g., single nucleotide variants, deletions, complex rearrangements) are not detectable by this assay.

Reference Range
See individual components
Ref. Range Notes

See individual components

FMR1 is located at chromosome Xq27.3. FMR1 alleles are categorized by number of CCG repeats and methylation status:

  • Non-expanded (“normal”) allele: up to 44 repeats
  • Intermediate (“gray zone”) allele: 45-54 repeats
  • Premutation allele: 55-200 repeats
  • Full expansion (“full mutation”) allele: over 200 repeats
References
  • Hall DA and O'Keefe JA. Clinical neurogenetics: fragile x-associated tremor/ataxia syndrome. Neurol Clin 2013, 31:1073-84. 24176424
  • Hunter JE, Berry-Kravis E, Hipp H, et al. FMR1 Disorders. 1998 Jun 16 [Updated 2019 Nov 21]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1384/
  • Monaghan KG, Lyon E, Spector EB, and erican College of Medical Genetics and Genomics. 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, 15:575-86. 23765048
  • Pirozzi F, Tabolacci E, and Neri G. The FRAXopathies: definition, overview, and update. Am J Med Genet A 2011, 155A:1803-16. 21739597
  • Sullivan SD, Welt C, and Sherman S. FMR1 and the continuum of primary ovarian insufficiency. Semin Reprod Med 2011, 29:299-307. 21969264
Guidelines

Ordering & Collection

Specimen Type
Blood, amniocytes, chorionic villus tissue or cultured cells.
Collection

BLOOD:

  • Adult: 5 mL LAVENDER TOP tube
  • Child: 2 mL LAVENDER TOP tube
  • Also acceptable: YELLOW TOP (ACD) tube
  • Unacceptable: Heparin green top tubes


AMNIOCYTES or CULTURED CHORIONIC VILLUS CELLS:

  • Two (2) T23 or One (1) T75 flask (minimum 1-T25 flask)

CHORIONIC VILLIS and/or TISSUE:

  • In sterile tube or culture media, at least 5 mg tissue.

Prenatal testing requires concomitant testing for maternal cell contamination (see Online Test Guide, Lab Mnemonic Maternal Cell Contamination [MCC] for ordering and specimen requirements)

Forms & Requisitions

Genetics Requisition

Handling Instructions

Blood: Refrigerate whole blood up to 1 week.

Amniocytes & cultured CVS cells: Hold flasks at room temperature.

Chorionic villi &/or tissue: Hold at room temperature.

Outside Laboratories: Ship whole blood at ambient temperature for receipt within 1 week of specimen collection. For cultured amniocytes or chorionic villus cells and for CVS or other tissue, transport and store at room temperature within 24 hours of obtaining CV or removing cultured cells from incubator.

Quantity
requested: Entire specimen
minimum: Blood: 3 mL. Amniocytes, cultured chorionic villus cells, chorionic villi or tissue: as above.

Processing

Processing

Please notify Genetics about amniocytes, cultured chorionic villus cells, chorionic villi or tissue.

Transport Temperature

Performance

LIS Dept Code
Genetics (GEN)
Performing Location(s)
UW-MT Genetics

Attention: Genetics Lab
Clinical lab, Room NW220
University of Washington Medical Center
1959 NE Pacific Street
Seattle, WA 98195

Tel: 206-598–6429 M–F (7:30 AM–4:00 PM)
Fax: 206-598–0304
Lab email: genelab@uw.edu

Tel (EXOME only): 206-543-0459

Manager

Joe Bernal, jbernal@uw.edu

Genetic Counselors

Angela Jacobson, MS, LGC agibson@uw.edu
Sandra Coe, MS,LGC, scoe20@uw.edu
Dru Leistritz, MS, LGC, dru2@uw.edu (EXOME testing only)
Daniel W. Serber, PhD, MS, LCGC, dwserber@uw.edu

Variant Review Scientist

Ankita Jhuraney, PhD
Sarah Paolucci, MA, MS, LGC, spaolucc@uw.edu
Catherine A. Darcey, MSc

Faculty

Colin C. Pritchard, MD, PhD
Brian H. Shirts, MD, PhD
Christina Lockwood, PhD, DABCC
Stephen Salipante, MD, PhD
Eric Konnick, MD, MS
Niklas Krumm, MD,PhD
Vera Paulson, MD, PhD
Jillian Buchan, PhD, FACMG
Frequency
Performed weekly. Results within 2-3 weeks.
Available STAT?
No

Billing & Coding

CPT codes
81243
LOINC
81856-7