The FMR1 mRNA contains the transcribed CGG-repeat tract as part of the 5 untranslated region, which hybridizes to the complementary CGG-repeat portion of the FMR1 gene to form an RNA·DNA duplex.A subset of people with intellectual disability and symptoms resembling fragile X syndrome are found to have point mutations in FMR1. This subset lacked the CGG repeat expansion in FMR1 traditionally associated with fragile x syndrome. Inheritance
Fragile X syndrome has traditionally been considered an X-linked dominant condition with variable expressivity and possibly reduced penetrance. However, due to genetic anticipation and X-inactivation in females, the inheritance of Fragile X syndrome does not follow the usual pattern of X-linked dominant inheritance, and some scholars have suggested discontinuing labeling X-linked disorders as dominant or recessive. Females with full FMR1 mutations may have a milder phenotype than males due to variability in X-inactivation.Before the FMR1 gene was discovered, analysis of pedigrees showed the presence of male carriers who were asymptomatic, with their grandchildren affected by the condition at a higher rate than their siblings suggesting that genetic anticipation was occurring. This tendency for future generations to be affected at a higher frequency became known as the Sherman paradox after its description in 1985. Due to this, male children often have a greater degree of symptoms than their mothers.The explanation for this phenomenon is that male carriers pass on their premutation to all of their daughters, with the length of the FMR1 CGG repeat typically not increasing during meiosis, the cell division that is required to produce sperm.
Of those with fragile X syndrome, prevalence of concurrent autism spectrum disorder (ASD) has been estimated to be between 15 and 60%, with the variation due to differences in diagnostic methods and the high frequency of autistic features in individuals with fragile X syndrome not meeting the DSM criteria for an ASD.Although individuals with FXS have difficulties in forming friendships, those with FXS and ASD characteristically also have difficulties with reciprocal conversation with their peers. Social withdrawal behaviors, including avoidance and indifference, appear to be the best predictors of ASD in FXS, with avoidance appearing to be correlated more with social anxiety while indifference was more strongly correlated to ASD. When both autism and FXS are present, a greater language deficit and lower IQ is observed as compared to children with only FXS.Genetic mouse models of FXS have also been shown to have autistic-like behaviors. Social interaction
FXS is characterized by social anxiety, including poor eye contact, gaze aversion, prolonged time to commence social interaction, and challenges forming peer relationships. Social anxiety is one of the most common features associated with FXS, with up to 75% of males in one series characterized as having excessive shyness and 50% having panic attacks.