Fragile X Mental Retardation

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General Information

Lab Name
Fragile X Mental Retardation
Lab Code
FX
Epic Ordering
FRAGILE X MENTAL RETARDATION
Description

Fragile X Syndrome (FXS)

FXS, the most common inherited cause of intellectual disability, affects about 1:3,000-4,000 males and 1:6,000-8,000 females. Affected males present with moderate intellectual disability, language delay, elongated facies, protruding ears, language delay, and in adults macroorchidism. Affected females typically have a milder phenotype of mild or moderate learning disability. In over 99% of cases, fragile X syndrome is caused by an FMR1 full mutation allele that is mutated by an expansion of CGG trinucleotide repeat to >200 and abnormally hypermethylated.

Fragile X Ataxia/Tremor Syndrome (FXTAS)

FXTAS may occur in males and females who have an FMR1 premutation and is characterized primarily by intention tremor, cerebellar gait ataxia, parkinsonism, and cognitive decline. FXTAS has a frequency in the US of about 1:4800. A diagnosis of FXTAS can be made by finding an FMR1 premutation allele in a person with late onset neurological disorder, even if mild. The penetrance of FXTAS in males over 50 years of age with an FMR1 premutation is about 40%; penetrance increases with advancing age. Penetrance in females over the age of 50 years is much lower, likely less than 10%.

Fragile X-Related Primary Ovarian Insufficiency (FXPOI)

FXPOI is the cessation of menses before age 40 years in a woman who has one FMR1 premutation allele with CGG trinucleotide repeats in the range from 54 to 200. The frequency in the US is about 1:3560. FXPOI occurs in approximately 12-28% of females who have an FMR1 premutation vs 1% of the general population. Among female with idiopathic POI about 6-8% have an FMR1 premutation. This disorder is sometimes referred to as fragile X- or FMR1-associated premature ovarian failure (POF), however because the phenotype is not always complete ovarian failure, POI is the preferred term.

Note: Female carriers of an FMR1 allele with <100 CGG repeats should 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 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
  • 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
  • Hall DA and O'Keefe JA. Clinical neurogenetics: fragile x-associated tremor/ataxia syndrome. Neurol Clin 2013, 31:1073-84. 24176424
  • 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
FMR1, FXTAS, Fragile X-associated tremor ataxia syndrome, POF, ataxia, autism, developmental delay, mental retardation, premature ovarian failure, primary ovarian insufficiency, tremor
Components

Interpretation

Method

The region of FMR1 containing the CGG trinucleotide repeat is amplified and the length measured by capillary electrophoresis against FMR1 alleles of known length using repeat primed PCR. Note: There are rare FMR1 mutations; less than 1% of individuals affected with FXS do not have a FMR1 full mutation but carry a deletion or point mutation in the FMR1 gene. These and other rare cases (e.g., point mutations) may not be detectable by this test.

Reference Range
See individual components
Ref. Range Notes

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

  • Normal alleles: 44 or fewer CGG repeats
  • Intermediate alleles: 45-54 CGG repeats
  • Premutation alleles: 55-200 CGG repeats
  • Full mutation alleles:greater than 200 CGG repeats along with hypermethylation
References
  • 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
  • Hall DA and O'Keefe JA. Clinical neurogenetics: fragile x-associated tremor/ataxia syndrome. Neurol Clin 2013, 31:1073-84. 24176424
  • 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.

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

Rebecca Gaulin, rgaulin@uw.edu

Genetic Counselors

Angela Jacobson, MS, LGC agibson@uw.edu
Sarah Paolucci, MA, MS, LGC, spaolucc@uw.edu
Jenna Huey, MS, LGC, jlhuey@uw.edu
Sandra Coe, MS,LGC, scoe20@uw.edu
Dru Leistritz, MS, LGC, dru2@uw.edu (EXOME testing only)

Variant Review Scientist

Ankita Jhuraney, PhD

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
Billing Comments

For pricing information, contact Client Support Services 206-520-4600 or 800-713-5198.

LOINC
21759-6