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22642 Fragile X Syndrome, Molecular Analysis (FXS)

Fragile X Syndrome, Molecular Analysis (FXS)
Test Code: FXMOLSO
Synonyms/Keywords
FMR1, Fragile X tremor ataxia syndrome, FXTAS, Martin-Bell Syndrome, POF, Premature ovarian failure, FXPB, POI, Premature ovarian insufficiency
Useful For

Confirmation of a diagnosis of fragile X syndrome, fragile X tremor/ataxia syndrome, or premature ovarian insufficiency caused by expansions in the FMR1 gene

Determination of carrier status for individuals with a family history of fragile X syndrome or X-linked intellectual disability

Prenatal diagnosis of fragile X syndrome when there is a documented FMR1 expansion in the family

Specimen Requirements
Specimen Type Preferred Container/Tube Acceptable Container/Tube Specimen Volume Specimen Minimum Volume
(allows for 1 repeat)
Pediatric Minimum Volume
(no repeat)
Submit only 1 of the following specimens:​ ​ ​ ​ ​ ​
Whole blood​ EDTA Lavender Top tube (LTT) or Yellow Top Tube (ACD)​ Any anticoagulant​ 3 mL​ 0.5 mL​
Amniotic fluid​ Amniotic fluid container​ 20 mL​ 10 mL​
Chorionic villi​ 15-mL tube containing 15 mL of transport media​ 20 mg​ 5 mg​
 Confluent cultured cells​ T-25 flask​ 2 flasks​
Collection Processing Instructions

Specimen must arrive within 96 hours of collection.

Whole blood:

1. Invert several times to mix blood.
2. Send specimen in original tube. 
 
Amniotic fluid:
Due to the complexity of prenatal testing, consultation with the laboratory is required for all prenatal testing. Prenatal specimens can be sent Monday through Thursday and must be received by 5 p.m. CST on Friday in order to be processed appropriately. All prenatal specimens must be accompanied by a maternal blood specimen. Order MCC/88636 Maternal Cell Contamination, Molecular Analysis on the maternal specimen.
 
Chorionic villi:
Additional Information: FMR1-methylation status cannot be assessed on some chorionic villus specimens. Contact a genetic counselor/consultant at Mayo Clinic Laboratories at 800-533-1710 to discuss the limitations of testing prior to sending a chorionic villus specimen for fragile X analysis.
 
Confluent cultured cells:
Submit confluent cultured cells from another laboratory.
Specimen Stability Information
Specimen Type Temperature
Whole blood​ ​ Ambient (preferred)​
Refrigerated​
Amniotic fluid​ ​ Ambient ​
Refrigerated​ (preferred)
Chorionic villi​ Refrigerated​
Confluent cultured cells​ ​ Ambient (preferred)​​
Refrigerated​
Interference

​For predictive testing, it is important to first document the presence of CGG-repeat amplification in the FMR1 gene in an affected family member to confirm that molecular expansion is the underlying mechanism of disease in the family.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

Methylation status will not be assessed on chorionic villus specimens nor will it be assessed if the reported gender is female. 

Less than 1% of individuals clinically diagnosed with fragile X syndrome do not have the CGG expansion-type mutation. These individuals may have a different type of mutation within the FMR1 gene (eg, deletion or point mutation). 

Due to incomplete penetrance and variable expression of the FMR1 expansion, this test is not reliable for prenatal assessment of disease severity.

The absence of an expansion in the FMR1 gene does not eliminate the diagnosis of other inherited disorders that have overlapping clinical features with fragile X syndrome, fragile X tremor/ataxia syndrome, or premature ovarian insufficiency.

Performing Laboratory Information
Performing Location Day(s) Test Performed Analytical Time Methodology/Instrumentation
Mayo Clinic Laboratories
Monday, Wednesday​
8-10 days
Polymerase Chain Reaction (PCR)-Based Assays
Reference Lab
Test Information

​Fragile X syndrome is an X-linked disorder with variable expression in males and females. In greater than 99% of affected individuals, it is caused by an expansion of the CGG trinucleotide repeat in the 5'UTR (untranslated region) of the FMR1 gene, located on the X chromosome. This trinucleotide repeat is polymorphic in the general population, with the number of repeats ranging from 5 to 44. These normal alleles are passed from generation to generation with the number of repeats remaining constant. Small expansions, called premutations, range from 55 to 200 CGG repeats. Individuals with a premutation do not exhibit features of fragile X syndrome but are at risk for other FMR1-related disorders such as fragile X tremor/ataxia syndrome (FXTAS) and premature ovarian insufficiency (POI). Transmission of a premutation by a male to his daughter usually results in little or no change in the CGG repeat number. Transmission of a premutation by a female to her son or daughter usually results in further expansion, either to a larger premutation or a full mutation. The risk for a female with a premutation to have a child affected with fragile X syndrome by expansion to a full mutation increases with the number of CGG repeats in the premutation. Full mutations are typically greater than 200 repeats long and are associated with abnormal methylation of a region adjacent to the FMR1 gene. This is thought to interfere with normal FMR1 gene expression, resulting in fragile X syndrome. There are multiple clinical phenotypes associated with expansion (premutations and full mutations) in the FMR1 gene.

Fragile X Syndrome:

Approximately 1 in 4000 individuals (male and female) are affected with fragile X syndrome. Most affected males exhibit moderate mental retardation with affected females having milder, if any, cognitive deficiency. Neuropsychiatric diagnoses, such as autism spectrum and anxiety disorders, are common. Characteristic physical features include a long face with prominent jaw, protruding ears, connective tissue abnormalities, and large testicles in postpubertal males.

Fragile X Tremor/Ataxia Syndrome (FXTAS):

FXTAS is a neurodegenerative disorder that is clinically distinct from fragile X syndrome. Both males and females with a premutation are at risk for FXTAS. However, the disorder is much less common and milder in clinical presentation than fragile X syndrome, and shows a later age of onset in females. Clinical hallmarks of the disorder include intention tremor, gait ataxia, dementia, and neuropsychiatric symptoms. The risk for FXTAS increases as the number of CGG repeats increases, and the majority of individuals with FXTAS have CGG repeat expansions of 70 or more. Penetrance of clinical symptoms is associated with increasing age, with the majority of affected males showing symptoms between age 70 and 90.

Premature Ovarian Insufficiency (POI):

Females with a premutation are at risk for increased follicular stimulating hormone (FSH) levels, early menopause, and POI. Penetrance and early onset of female reproductive symptoms correlates with increasing size of the CGG repeat and reaches its highest penetrance at approximately 80 to 90 repeats. Of note, penetrance actually remains stable or may even decrease at approximately 100 repeats. There is no risk for increased penetrance of the POI phenotype due to maternal or paternal inheritance of the expanded CGG repeat.

Reference Range Information

Normal alleles: 5-44 CGG repeats

Intermediate (grey zone) alleles: 45-54 CGG repeats

Premutation alleles: 55-200 CGG repeats

Full mutation alleles: >200 CGG repeats

An interpretive report will be provided.

 

Methylation status:

Unmethylated: < or =20%

Partially methylated: 21-69%

Fully methylated: > or =70%

Interpretation
​An interpretive report will be provided.
Outreach CPTs
CPT Modifier
(if needed)
Quantity Description Comments
​81243
​88233 ​Fibroblast Culture - Tissue Culture Skin/Biopsy ​as needed
​88240 ​Fibroblast Culture - Cell Cryopreserve/Storage ​as needed
​88235 ​Amniotic Fluid Culture/Genetic Test - Amniotic Fluid or Chorionic ​as needed
​88240 ​Amniotic Fluid Culture/Genetic Test - Cryopreservation ​as needed
​81265 ​Maternal Cell Contamination ​as needed
​81244 ​Fragile X, Follow-up Analysis ​as needed
Synonyms/Keywords
FMR1, Fragile X tremor ataxia syndrome, FXTAS, Martin-Bell Syndrome, POF, Premature ovarian failure, FXPB, POI, Premature ovarian insufficiency
Ordering Applications
Ordering Application Description
​Centricity ​Fragile X-Mole
​Cerner ​Fragile X Molecular Analysis (9569)
​COM ​Fragile X Chrom/Mole Bld, Mayo
If the ordering application you are looking for is not listed, contact your local laboratory for assistance.
Specimen Requirements
Specimen Type Preferred Container/Tube Acceptable Container/Tube Specimen Volume Specimen Minimum Volume
(allows for 1 repeat)
Pediatric Minimum Volume
(no repeat)
Submit only 1 of the following specimens:​ ​ ​ ​ ​ ​
Whole blood​ EDTA Lavender Top tube (LTT) or Yellow Top Tube (ACD)​ Any anticoagulant​ 3 mL​ 0.5 mL​
Amniotic fluid​ Amniotic fluid container​ 20 mL​ 10 mL​
Chorionic villi​ 15-mL tube containing 15 mL of transport media​ 20 mg​ 5 mg​
 Confluent cultured cells​ T-25 flask​ 2 flasks​
Collection Processing

Specimen must arrive within 96 hours of collection.

Whole blood:

1. Invert several times to mix blood.
2. Send specimen in original tube. 
 
Amniotic fluid:
Due to the complexity of prenatal testing, consultation with the laboratory is required for all prenatal testing. Prenatal specimens can be sent Monday through Thursday and must be received by 5 p.m. CST on Friday in order to be processed appropriately. All prenatal specimens must be accompanied by a maternal blood specimen. Order MCC/88636 Maternal Cell Contamination, Molecular Analysis on the maternal specimen.
 
Chorionic villi:
Additional Information: FMR1-methylation status cannot be assessed on some chorionic villus specimens. Contact a genetic counselor/consultant at Mayo Clinic Laboratories at 800-533-1710 to discuss the limitations of testing prior to sending a chorionic villus specimen for fragile X analysis.
 
Confluent cultured cells:
Submit confluent cultured cells from another laboratory.
Specimen Stability Information
Specimen Type Temperature
Whole blood​ ​ Ambient (preferred)​
Refrigerated​
Amniotic fluid​ ​ Ambient ​
Refrigerated​ (preferred)
Chorionic villi​ Refrigerated​
Confluent cultured cells​ ​ Ambient (preferred)​​
Refrigerated​
Interference

​For predictive testing, it is important to first document the presence of CGG-repeat amplification in the FMR1 gene in an affected family member to confirm that molecular expansion is the underlying mechanism of disease in the family.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

Methylation status will not be assessed on chorionic villus specimens nor will it be assessed if the reported gender is female. 

Less than 1% of individuals clinically diagnosed with fragile X syndrome do not have the CGG expansion-type mutation. These individuals may have a different type of mutation within the FMR1 gene (eg, deletion or point mutation). 

Due to incomplete penetrance and variable expression of the FMR1 expansion, this test is not reliable for prenatal assessment of disease severity.

The absence of an expansion in the FMR1 gene does not eliminate the diagnosis of other inherited disorders that have overlapping clinical features with fragile X syndrome, fragile X tremor/ataxia syndrome, or premature ovarian insufficiency.

Useful For

Confirmation of a diagnosis of fragile X syndrome, fragile X tremor/ataxia syndrome, or premature ovarian insufficiency caused by expansions in the FMR1 gene

Determination of carrier status for individuals with a family history of fragile X syndrome or X-linked intellectual disability

Prenatal diagnosis of fragile X syndrome when there is a documented FMR1 expansion in the family

Reference Range Information

Normal alleles: 5-44 CGG repeats

Intermediate (grey zone) alleles: 45-54 CGG repeats

Premutation alleles: 55-200 CGG repeats

Full mutation alleles: >200 CGG repeats

An interpretive report will be provided.

 

Methylation status:

Unmethylated: < or =20%

Partially methylated: 21-69%

Fully methylated: > or =70%

Interpretation
​An interpretive report will be provided.
For more information visit:
Performing Laboratory Information
Performing Location Day(s) Test Performed Analytical Time Methodology/Instrumentation
Mayo Clinic Laboratories
Monday, Wednesday​
8-10 days
Polymerase Chain Reaction (PCR)-Based Assays
Reference Lab
For billing questions, see Contacts
Outreach CPTs
CPT Modifier
(if needed)
Quantity Description Comments
​81243
​88233 ​Fibroblast Culture - Tissue Culture Skin/Biopsy ​as needed
​88240 ​Fibroblast Culture - Cell Cryopreserve/Storage ​as needed
​88235 ​Amniotic Fluid Culture/Genetic Test - Amniotic Fluid or Chorionic ​as needed
​88240 ​Amniotic Fluid Culture/Genetic Test - Cryopreservation ​as needed
​81265 ​Maternal Cell Contamination ​as needed
​81244 ​Fragile X, Follow-up Analysis ​as needed
For most current information refer to the Marshfield Laboratory online reference manual.