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 must arrive within 96 hours of collection.
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.
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.
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.
Unmethylated: < or =20%
Partially methylated: 21-69%
Fully methylated: > or =70%