FXS is primarily caused by mutations in the Fragile X Mental Retardation 1 (FMR1) gene, located on the long arm of the X chromosome (Xq27.3). The FMR1 gene encodes the Fragile X Mental Retardation Protein (FMRP), which plays a crucial role in synaptic plasticity and protein synthesis regulation in the brain. Specifically, FMRP is involved in modulating the translation of numerous synaptic proteins essential for neuronal development and function.

The hallmark genetic abnormality in FXS is the expansion of a trinucleotide CGG repeat sequence in the 5′-untranslated region (UTR) of the FMR1 gene. In unaffected individuals, this CGG repeat sequence typically ranges from 5 to 44 repeats. However, in individuals with FXS, the CGG repeat sequence is expanded beyond a certain threshold, usually consisting of 200 or more repeats. This expansion leads to hypermethylation of the FMR1 gene promoter region, resulting in transcriptional silencing and a deficiency or absence of FMRP production.

The mutational mechanism underlying FXS involves the instability of CGG repeat tracts, particularly within the premutation range of 55 to 200 repeats. Premutation alleles are meiotically unstable and can expand to full mutations with over 200 repeats in subsequent generations, leading to the characteristic features of FXS. Notably, expansion to the full mutation range typically occurs during maternal transmission, as the full mutation cannot be maintained during spermatogenesis.

Furthermore, FXS exhibits an X-linked inheritance pattern, meaning the mutated FMR1 gene is located on the X chromosome. Males, who have only one X chromosome, are more severely affected by FXS compared to females, who have two X chromosomes. In females, the presence of a normal X chromosome can partially compensate for the mutated X chromosome through X-chromosome inactivation, resulting in a milder phenotype.

Understanding the intricate molecular and genetic mechanisms underlying FXS is essential for accurate diagnosis, genetic counseling, and the development of targeted therapies aimed at addressing the underlying molecular abnormalities associated with the disorder. Ongoing research continues to elucidate the pathophysiology of FXS, with the ultimate goal of improving treatment strategies and enhancing the quality of life for individuals affected by this condition.