Abstract
The FMR1 premutation is of increasing interest to the FXS community, as questions about a primary premutation phenotype warrant research attention. 100 FMR1 premutation carrier mothers (mean age = 58; 67–138 CGG repeats) of adults with fragile X syndrome were studied with respect to their physical and mental health, motor, and neurocognitive characteristics. We explored the correlates of CGG repeat mosaicism in women with expanded alleles. Mothers provided buccal swabs from which DNA was extracted and the FMR1 CGG genotyping was performed (Amplidex Kit, Asuragen). Mothers were categorized into three groups: Group 1: premutation non-mosaic (n = 45); Group 2: premutation mosaic (n = 41), and Group 3: premutation/full mutation mosaic (n = 14). Group 2 mothers had at least two populations of cells with different allele sizes in the premutation range besides their major expanded allele. Group 3 mothers had a very small population of cells in the full mutation range (>200 CGGs) in addition to one or multiple populations of cells with different allele sizes in the premutation range. Machine learning (random forest) was used to identify symptoms and conditions that correctly classified mothers with respect to mosaicism; follow-up comparisons were made to characterize the three groups. In categorizing mosaicism, the random forest yielded significantly better classification than random classification, with overall area under the receiver operating characteristic curve (AUROC) of 0.737. Among the most important symptoms and conditions that contributed to the classification were anxiety, menopause symptoms, executive functioning limitations, and difficulty walking several blocks, with the women who had full mutation mosaicism (Group 3) unexpectedly having better health. Although only 14 premutation carrier mothers in the present sample also had a small population of full mutation cells, their profile of comparatively better health, mental health, and executive functioning was unexpected. This preliminary finding should prompt additional research on larger numbers of participants with more extensive phenotyping to confirm the clinical correlates of low-level full mutation mosaicism in premutation carriers and to probe possible mechanisms.
Highlights
Variation in the number of CGG repeats in the FMR1 gene has received increasing research attention during the past three decades
This paper reports on another factor that may be relevant to the phenotypic heterogeneity of the FMR1 premutation phenotype, namely mosaicism
Phenotypic data were available with respect to health, psychiatric, motor, and neurocognitive characteristics, making it possible to explore genotype–phenotype correlations associated with mosaicism
Summary
Variation in the number of CGG repeats in the FMR1 gene has received increasing research attention during the past three decades. Depending on the specific symptom, severity of clinical involvement is associated with the number of CGG repeats Some symptoms, such as FXTAS, are more severe at the upper end of the premutation range, likely due to RNA toxicity (Tassone et al, 2007; Leehey et al, 2008; Hagerman and Hagerman, 2013), while other symptoms, such as FXPOI, depression, and anxiety, may be more severe in the middle of the premutation range (Ennis et al, 2006; Allen et al, 2007; Seltzer et al, 2012; Mailick et al, 2014b). Phenotypic data were available with respect to health, psychiatric, motor, and neurocognitive characteristics, making it possible to explore genotype–phenotype correlations associated with mosaicism This is an exploratory study, based on Pretto et al (2014) our expectation was that those with full mutation mosaicism would be more severely affected by impairments in health, psychiatric, motor, and neurocognitive characteristics than premutation carriers who were non-mosaic or were mosaic for only premutation size alleles
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
