Fragile X syndrome (FXS) is a genetic condition that impacts intellectual development and can lead to behavioral and learning challenges. It is the most common inherited cause of intellectual disability, affecting males more frequently and with greater severity than females. FXS arises from a change in the FMR1 gene on the X chromosome. This gene produces a protein called FMRP, important for brain development and communication between brain cells.
Defining FMR1 Allele Sizes
The FMR1 gene contains a segment of DNA with repeated CGG units. The number of these CGG repeats determines gene function and categorizes FMR1 alleles. Four main classifications exist based on repeat count.
Normal alleles have 5 to 44 CGG repeats. These alleles are stable, meaning the number of repeats usually remains consistent when passed from parent to child. An intermediate allele has 45 to 54 CGG repeats. This range is higher than normal but not extensive enough for a premutation classification.
Premutation alleles contain 55 to 200 CGG repeats. These alleles are unstable and can expand when passed to the next generation. Full mutation alleles have over 200 CGG repeats, often ranging from several hundred to several thousand. This extensive expansion causes the FMR1 gene to “turn off” or become silenced, leading to FMRP protein absence or deficiency, resulting in Fragile X syndrome.
Living with an Intermediate Allele
Individuals with an intermediate allele generally do not experience symptoms of Fragile X syndrome. They are not at risk for the intellectual disability or developmental delays characteristic of the full mutation. These individuals also typically do not develop Fragile X-associated primary ovarian insufficiency (FXPOI) or Fragile X-associated tremor/ataxia syndrome (FXTAS), which are conditions sometimes seen in premutation carriers.
The primary consideration for an intermediate allele is its potential for instability during transmission to future generations. While most intermediate alleles are stable, a small percentage (around 14%) may increase in repeat size when passed from a mother to her child. This expansion, though usually minor, means that over several generations, an intermediate allele could expand into a premutation allele.
Expansion risk is influenced by intermediate allele size and “AGG interruptions” within the CGG repeat sequence, which can make the gene more stable. The gene is more unstable when transmitted from a mother than from a father. Therefore, while an intermediate allele does not cause current health issues for the carrier, its significance is mainly related to reproductive planning and potential allele expansion in descendants.
Genetic Testing and Guidance
FMR1 allele sizes, including intermediate alleles, are identified through genetic testing methods. The standard approach involves DNA analysis, primarily using a combination of Polymerase Chain Reaction (PCR) and Southern blot analysis. PCR is effective for determining precise CGG repeat numbers for normal, intermediate, and premutation alleles. Southern blot analysis is used for characterizing larger repeat expansions and assessing the methylation status of the gene, which indicates if the gene is “turned off.”
Genetic testing for FMR1 is recommended for individuals with unexplained developmental delay, intellectual disability, or autism spectrum disorder, even if there is no known family history of FXS. Testing is also considered for females who are pregnant or planning a pregnancy, especially if they have a family history of Fragile X-associated disorders, unexplained ovarian failure, or early menopause. Family members of individuals diagnosed with an FMR1 full mutation or premutation should also consider testing to understand their carrier status.
Genetic counseling is an important step both before and after FMR1 genetic testing. Genetic counselors provide comprehensive information about the inheritance patterns of Fragile X syndrome, explain the implications of test results, and discuss reproductive risks and family planning options. They offer personalized support and help individuals understand complex concepts, ensuring informed decision-making regarding their health and their family’s genetic future.