Fragile-X syndrome

Fragile X syndrome (FXS) is an inherited disorder that causes intellectual disability, behavioral challenges and various physical characteristics. Though FXS occurs in both genders, males are more frequently affected than females, and generally with greater severity. Most males and some females with fragile X syndrome have characteristic physical features that become more apparent with age. These features include a long and narrow face, large ears, a large jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles after puberty. The degree of intellectual disability and type of behavioral challenges varies from person to person. No specific treatment is available. Life expectancy is unaffected by FXS. FXS is caused by an expansion of repetitive repeat region of the FMR1 gene.

Fragile X syndrome is inherited in an X-linked manner. This type of inheritance requires the presence of one copy of a pathogenic variant in the gene located on the X-chromosome for males to be affected. When the pathogenic variant is inherited from the unaffected carrier mother, the male child will have the genetic disease. There is a 50% chance that a baby will inherit the pathogenic variant from the mother; females who inherit the pathogenic variant will be carriers, males who inherit the pathogenic variant will be affected.

Almost all cases of Fragile X syndrome involve a short DNA segment known as the CGG trinucleotide repeat in the Fragile X Mental Retardation (FMR1) gene. The number of times the CGG sequence is repeated determines the risk for Fragile X. This number is generally stable across generations. However in some circumstances, the number of repeats may increase (called expansion) between a parent and a child. Normally 5 to 44 CGG repeats are present in the FMR1 gene and that number generally remains stable between parent and child. A person who has 45 to 54 CGG repeats has an "intermediate size" and there is a small chance that the number of repeats may expand from parent to child. A person who has 55-200 CGG repeats has a "prepathogenic variant size." Female carriers with a prepathogenic variant have an increased risk of disorders called fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS). They are also considered to be at risk for having children affected with Fragile X syndrome as there is an increased chance that the number of repeats may expand between the parent and their child. Males who carry the perpathogenic variant are also at increased risk for FXTAS. A female carrier who has 200+ CGG repeats, a "full expansion", may exhibit, in variable degree, some or all symptoms of FXS.

FXS is the most common form of inherited intellectual disability in males and a significant cause of intellectual disability in females. The syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females.

Genetics Home Reference: Fragile X syndrome (http://ghr.nlm.nih.gov/)
Genetic Alliance: Fragile X syndrome (http://www.diseaseinfosearch.org/)

OMIM [FMR1: 300624, 300623, 311360] (http://www.ncbi.nlm.nih.gov/omim)
Gene Reviews: FMR1-Related Disorders (http://www.ncbi.nlm.nih.gov/books/NBK1116/)

• CGG repeat analysis