Fragile X Syndrome, Molecular Analysis
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Fragile X syndrome is an X-linked disorder with variable expression in males and females. It is caused by an expansion of the CGG trinucleotide repeat in 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, most often range from 59 to 200 CGG repeats. Premutation carriers 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 failure (POF). 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 premutation carrier 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 can be 200 to thousands of 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 1/4000 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 male and female premutation carriers are at risk for FXTAS. However, the disorder is much less common, milder in presentation, 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 failure (POF)
Female premutation carriers are at risk for increased follicular stimulating hormone (FSH) levels, early menopause, and POF. 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 POF phenotype due to maternal or paternal inheritance of the expanded CGG repeat.
Determination of carrier status for individuals with a family history of fragile X syndrome or X-linked mental retardation
Confirmation of a diagnosis of fragile X syndrome, fragile X tremor/ataxia syndrome, or premature ovarian failure caused by expansions in the FMR1 gene
Prenatal diagnosis of fragile X syndrome when there is a documented FMR1 expansion in the family
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
For predictive testing, it is important to first document the presence of a 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 cannot be assessed on chorionic villus specimens.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.
Less than 1% of individuals clinically diagnosed with fragile X syndrome do not have the CGG amplification-type mutation. These individuals may have a different type of mutation within the FMR1 gene (eg, deletion or point mutation) or a mutation in another gene.
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 failure.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
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.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Jacquemont S, Hagerman RJ, Hagerman PJ, Leehey MA: Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. Lancet Neurol 2007;6(1):45-55
2. Mc-Conkie-Rosell A, Finucane B, Cronister A, et al: Genetic counseling for fragile X Syndrome: updated recommendations of the National Society of Genetic Counselors. J Genet Couns 2005;14(4):249-270
3. Sherman S, Pletcher BA, Driscoll DA: Fragile X syndrome: diagnostic and carrier testing (ACMG Practice Guideline). Genet Med 2005;7:584-587