Non-CGG trinucleotide repeat expansions as pathogenic genetic mutations in Fragile X Syndrome

PurposeFragile X syndrome (FXS) is a hereditary genetic condition, caused by the expansion of the trinucleotide CGG repeated over 200 times (full mutation) in the 5UTR (untranslated region) regulatory region of the FMR1 gene, which leads to the absence of FMRP protein. Although the clinical standard genetic confirmation for FXS diagnosis is limited to the repeats, the use of gene sequencing techniques allowed the identification of genetic variants that occur throughout the entire FMR1 gene, including protein-coding and 3UTR gene regions. These mutations may also cause the inactivation of FMR1 gene, leading to the FXS phenotypes in individuals with CGG repeat expansions at a normal level (5-44 repeats) or at the premutation level (between 55 and 200 repeats), and not necessarily diagnosed with FXS. MethodsTo investigate how widespread the genetic mutations occurring throughout the FMR1 gene locus are, we performed a Systematic Literature Review (SLR) to identify and synthesize a catalog of disease-causing mutations in the gene that are related to cause FXS or correlated conditions. ResultsAfter a detailed literature analysis, we found 44 single nucleotide variants (SNV) at the locus of the FMR1 gene associated with developmental delay and/or intellectual disability, also including characteristics of FXS. Deletions involving the FMR1 gene that remove several other genes were also found to be associated with FXS phenotype and ovarian problems, besides cases of mosaicisms with deletions and a case of germline mosaicism. Moreover, several of the mutations found, although occurring in distinct parts of FMR1 gene, can alter the aminoacid sequence of FMRP protein. ConclusionOur critical review presents several non-CGG repeat mutations in FMR1 gene that are directly involved in the phenotypes found in Fragile X Syndrome, indicating that genetic screening for this neurodevelopmental condition should not be restricted to the CGG repeats.