Women with the FMR1 premutation: a within-family observational sibling study

Introduction Understanding the relative risk of the fragile X messenger ribonucleoprotein 1 (FMR1) premutation (PM) versus the risk of the PM and parenting a child with fragile X syndrome (FXS) is critical for PM carriers, their families and clinicians. For this study, we compared women with the PM with their biological sisters; some sisters also had the PM and some had normal-range cytosine–guanine–guanine (CGG) repeats. The sisters were further differentiated by whether they had a child with FXS.Methods This study of 67 women from 30 families used multilevel modelling to probe the effects of the PM with or without parenting a child with FXS, with strong control for family-of-origin factors and background genetics.Results Controlling for the false discovery rate, we found that mothers with the PM who had children with FXS were similar to their sisters who had the PM but did not have a child with FXS in health, sleep, social relationships, depressive symptoms and executive functioning, differing only in anxiety and stress. However, there were many differences when mothers with the PM who had children with FXS were compared with their sisters with normal-range CGGs, including greater fragile X-associated tremor/ataxia syndrome-type, depressive and anxiety symptoms, poorer sleep, greater negative support and greater stress.Conclusions In this study, the effect of the PM was stronger than the effect of parenting a child with FXS. Thus, the PM phenotype should not be primarily attributed to the effect of parenting a child with FXS. Additionally, by comparing mothers who had the PM and children with FXS with their sisters without the PM, the findings confirmed the effect of this dual vulnerability and here the vulnerability emerged even with strong familial controls.