PROJECT SUMMARY
The overarching goal of our proposal is to answer the clinically significant question: Does a fragile X
premutation (PM; an allele of 55-200 CGG repeats in the X-linked FMR1 gene) pose a significant risk to
childhood development? Why is this important? At least one in 300 women in the US carries a PM allele.
Because most of these alleles are small and not prone to large expansions, nearly half of children born to
these women will inherit a PM, whereas fewer than 6% will inherit a full mutation (>200 repeats), the allele that
causes fragile X syndrome. PM alleles are known to increase the risk for two late-onset disorders: fragile X
associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI).
Adults with a PM allele who do not have FXTAS or FXPOI are still reported to have executive skill and working
memory deficits, visuospatial weakness and poor math skills, anxiety, and depression. For children who carry a
PM, there is a significant gap in our knowledge. Some reports find higher rates of developmental delay,
attention deficits, autism, and anxiety among children with a PM versus non-carriers, but these reports are
limited by ascertainment bias and small sample size. We hypothesize that the toxic effect of a PM can manifest
early in life, leading to adverse neurodevelopmental outcomes and we propose to test this rigorously and
thoroughly. To address this gap in knowledge, we have an outstanding opportunity to study a large cohort of
children, now age 3 -12 years, who were identified prospectively: specifically, 582 children with a PM and 958
non-carriers, all identified when their carrier mothers underwent prenatal diagnosis for a fragile X mutation.
This unique cohort of children has minimal potential for ascertainment bias. In Aim 1, parents will complete
online questionnaires to describe their child’s general health and history of diagnosed neurodevelopmental
problems and to detail—using standardized questionnaires—the child’s behavior, executive skills, and social
relatedness. In Aim 2, a subset of school-aged participants who live in the mid-Atlantic region will be assessed
individually primarily via remote-administered semi-structured interview and neuropsychological measures
examining cognitive, academic, social and psychological function. Mothers will also complete questionnaires
regarding their own psychological well-being and parenting stress. We will evaluate all phenotypes with
respect to sex, CGG repeat length, and repeat structure to gain insight into the mechanisms and associated
risks (Aim 3). Our primary hypothesis is that children with a PM have a higher frequencies of
neurodevelopmental deficits than non-carrier children, stratified by sex. The combination of parental report and
direct assessment will provide a comprehensive evaluation of cognitive and behavioral skills. This will result in
a powerful combination of detailed phenotypic and genetic information that will unambiguously define the risk
of adverse childhood development posed by a PM allele.
