Investigation of phenotypes associated with mood and anxiety among male and female fragile X premutation carriers

The fragile X disorder spectrum, due to a CGG expansion in FMR1, includes fragile X syndrome (> 200 repeats) and the premutation-associated disorders of ovarian insufficiency and tremor/ataxia syndrome (similar to 55-199 repeats). Altered neurobehavioral profiles including variation of phenotypes associated with mood and anxiety may be expected among younger premutation carriers given this spectrum of disorders. However, previous studies have produced conflicting findings, providing the motivation to examine these phenotypes further. We investigated measures of mood and anxiety in 119 males and 446 females age 18-50 ascertained from families with a history of fragile X syndrome and from the general population. Scores were analyzed using a linear model with repeat length as the main predictor, adjusting for potential confounders. Repeat length was not associated with anxiety, but was marginally associated with depression and negative affect in males and negative affect only in females. These results suggest that premutation carriers may be at risk for emotional morbidity; however, phenotypic differences were subtle and of small effect size.