Background The clinical phenotypes of females with fragile X full mutations vary drastically. Comparisons of discordant monozygotic twins provide opportunities to ascertain crucial factors that influence disease phenotype penetrance.

Objective To identify crucial factors influencing the phenotypic expression of fragile X syndrome (FXS).

Methods and results We describe a pair of discordant monozygotic female twins (dichorionic–diamniotic, Di–Di) with full mutation. The degrees of their phenotypic discordance regarding physical, psychiatric and behavioural features were quantified in a series of neuropsychological tests that varied significantly. Their FMR1 expression levels and whole genome DNA methylation profiling in blood were similar. Their similar life experiences also suggested that environmental factors had limited influence. However, the skewed inactivation of the normal X chromosome in the hair roots of twin A, resulting in large reduction in FMR1 expression compared to that of twin B, could adequately explain their widely variable phenotypes.

Conclusions The sixfold variation in hair root FMR1 expression, which reflected FMRP (fragile X mental retardation protein) expression in the brain, accounted for the disparate phenotypes in IQ, cognition, and social capability between the twins. Additionally, considering the Di–Di type twinning and different CGG repeat sizes, CGG expansion should occur before splitting at day 3 of gestation.