Depression Symptom Trajectories in Mothers With the FMR1 Premutation Vary by CGG Repeat Length: A Longitudinal Study of 73 Women Spanning 20-75 Years of Age

Am J Med Genet B Neuropsychiatr Genet. 2025 May 26:e33033. doi: 10.1002/ajmg.b.33033. Online ahead of print.

ABSTRACT

Women with the FMR1 premutation (FXpm) are at heightened genetic vulnerability for depression, with risk compounded by the stressors of parenting a disabled child. Although risk factors persist as FXpm women age, depression in FXpm mothers during midlife and old age is poorly characterized. This study used an accelerated longitudinal design to capture the trajectory of depressive symptoms in 73 FXpm mothers across 20-75 years of age. The FXpm mothers had children with fragile X syndrome or FXpm and contributed 2-11 longitudinal assessments, for a total of 294 observations. Mothers with mid-range CGG expansions (91-110 CGG repeats) exhibited the highest overall symptoms, with a marked increase in depression during early midlife, followed by late midlife trajectories that varied by history of premature menopause. Symptoms of mothers with high CGGs (111-200) peaked during early and late adulthood rather than midlife. At low CGGs (55-90) symptoms were low and stable across age. Parenting stress was associated with increased symptoms during early adulthood, but this effect dwindled with age. Findings illuminate evolving patterns of depression vulnerability across adulthood that are shaped by specific environmental and genetic factors, offering insights for personalized medicine to enhance the health of aging FXpm mothers.

PMID:40418066 | DOI:10.1002/ajmg.b.33033