Fragile X syndrome full mutation in cognitively normal male identified as part of an Australian reproductive carrier screening program.

Fragile X syndrome (FXS) is caused by CGG expansions of ≥200 repeats (full mutation: FM). Typically, FM causes abnormal methylation of the FMR1 promoter and silencing of FMR1, leading to reduction of FMRP, a protein essential for normal neurodevelopment. However, if unmethylated, these alleles cause over-expression of FMR1 mRNA which has been associated with Fragile X Tremor and Ataxia Syndrome (FXTAS), a late onset disorder. This report details the molecular and clinical profile of an asymptomatic male (29 years) identified as a result of cascade testing who was found to have a rare unmethylated FM (UFM) allele, as well as premutation (PM: 55-199 CGG) size alleles in multiple tissues. Full-scale IQ was within the normal range and minimal features of autism were observed. Southern blot analysis identified FM smears in blood (220-380 CGG) and saliva (212-378 CGG). A PM of 159 CGG was identified in blood and saliva. FMR1 promoter methylation analysis showed all alleles to be unmethylated. FMR1 mRNA levels were greater than fivefold of median levels in typically developing controls and males with FXS mosaic for PM and FM alleles. Issues raised during genetic counseling related to risk for FXTAS associated with UFM and elevated FMR1 mRNA levels, as well as, reproductive options, with implications for future practice.