Spectrum of Syndromal Disorders Associated with Expansion of CGG Repeats of the FMR1 Gene Promoter: Pathogenetic Mechanisms and Clinical Manifestations

The class X-associated spectrum disorders (FXSD) combines the following clinical syndromes: fragile X chromosome-linked mental retardation syndrome (fragile X syndrome, FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and a group of neuropsychiatric disorders (fragile X-associated neuropsychiatric disorders, FXAND). These syndromes occur as a result of dynamic mutations of the FMR1 gene caused by expansion of trinucleotide repeats in the gene promoter. FXS syndrome (mental retardation, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD)) occurs when the FMR1 gene is completely mutated (an increase in the number of CGG repeats to more than 200), which is accompanied by full or partial suppression of FMRP protein expression. The clinical manifestations of FXTAS, FXPOI, and FXAND can occur in individuals carrying the FMR1 premutation (CGG repeats in the range 55–200). The main pathogenetic mechanisms of these diseases include a decrease in FMRP expression and accumulation of FMR1 mRNA containing an increased number of repeats. This review analyzes genophenotypic relationships within the spectrum of conditions associated with FMR1 dynamic mutations. An analysis of the relationship between the molecular mechanisms (FMRP defi ciency, translation of atypical isoforms, increased function of FMR1 mRNA) and clinical manifestations (level of cognitive development, severity of ASD, severity of symptoms of FXTAS, FXPOI and FXAND)is presented. © 2023, Springer Nature Switzerland AG.