Title: Health Profiles of Mosaic versus Non-Mosaic FMR1 Premutation Carrier Mothers of Children with Fragile X Syndrome
Legend: One hundred participants are arrayed on the x-axis, each case individually. Participants are ordered by mosaicism group: first, premutation (PM) non-mosaic (Group 1, in red), then PM mosaic (Group 2, in blue), and finally premutation/full mutation (FM) mosaic (Group 3, in green). Within each group, participants are ordered from lowest to highest numbers of CGG repeats. For Groups 2 and 3, large circles signify predominant premutation CGGs; small circles signify mosaicism.
Citation: Mailick M, Movaghar A, Hong J, Greenberg JS, DaWalt LS, Zhou L, Jackson J, Rathouz P, Baker MW, Brilliant M, Page D, Berry-Kravis EM (Under Review). Health profiles of mosaic versus non-mosaic FMR1 premutation carrier mothers of children with fragile X syndrome. Frontiers in Genetics.
Abstract: The FMR1 premutation is of increasing interest to the fragile X syndrome (FXS) community, as questions about a primary premutation phenotype warrant research attention. One hundred FMR1 premutation carrier mothers (mean age = 58; 67 to 138 CGG repeats) of adults with fragile X syndrome were studied with respect to their physical and mental health, and 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. Mothers were categorized into 3 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 2 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.
About the Lab: The focus of Mailick’s research is on the life course trajectory of developmental disabilities. She is interested in how the behavioral phenotypes of specific developmental disabilities, including autism, FXS, and Down syndrome, change during adolescence, adulthood, and old age. In addition, she studies how family environment affects the development of individuals with disabilities during these stages of life, and reciprocally how parents and siblings of individuals with disabilities are affected. Her current research includes three projects: a 14-year longitudinal study of autism during adolescence and adulthood; research on a demographically-representative sample of parents of individuals with developmental disabilities; and a study of family adaptation to FXS. She recently completed an epidemiological study of the premutation of FXS and a 20-year follow-up of a cohort of older adults with Down syndrome, examining how family environment predicts outcomes in midlife and old age. Together, these studies offer specific insights about developmental disabilities across the life course, and the impacts on families.