This document addresses mosaicism in Fragile X syndrome (FXS), though it should be noted that mosaicism is observed in many genetic conditions. In Fragile X syndrome, both “size” and “methylation” mosaicism are seen.
Size mosaicism is defined as having both premutation and full mutation repeat expansions in the FMR1 gene. In methylation mosaicism, some cells are methylated, and some are not, resulting in the production of some (varying amounts of) FMRP.
Fragile X syndrome is a genetic condition that can cause learning disabilities, developmental delays, and social and behavioral issues. Significant anxiety is also very common in Fragile X syndrome. Although Fragile X syndrome occurs in both genders, males are more frequently and typically more severely affected than females. Fragile X syndrome is the most common cause of inherited intellectual and developmental disability and the most common, known single-gene cause of autism spectrum disorder (ASD).
Fragile X syndrome is caused by a DNA expansion in the FMR1 gene, which is located on the X chromosome. The FMR1 gene includes a repeated DNA code commonly referred to as CGG repeats, as it is composed of DNA elements called cytosine-guanine-guanine (CGG). Most everyone has the FMR1 gene as well as these CGG repeats and typically there are up to 45 CGG repeats, with people in the general population commonly having around 30 CGG repeats. Some people have a small expansion in the gene, with a range of 45–54 CGG repeats, which is also known as an intermediate or gray zone expansion. Individuals with larger expansions may have a premutation (55–200 CGG repeats) or a full mutation (more than 200 CGG repeats). Most people with FMR1 full mutations show symptoms of Fragile X syndrome.
When the FMR1 gene has >200 CGG repeats (full mutation), a process called methylation occurs that turns the gene off so it cannot make its protein product, FMRP, and thus results in decreased or absent FMRP; it is FMRP that is needed for typical brain development and functioning. Symptoms of Fragile X syndrome are typically caused by the absence of FMRP due to complete methylation of the FMR1 gene when there is a full mutation present.