The absence of AGG Interruptions Is A Risk Factor for Full Mutation Expansion Among Israeli FMR1 Premutation Carriers

BACKGROUND: Screening for the FMR1 premutation carrier state is free of charge and recommended in Israel for every woman who wishes to conceive in order to prevent Fragile X Syndrome (FXS) in her offspring. The number of AGG interruptions in the premutation allele has been suggested to influence allele stability.

Aim: To assess the role of AGG interruptions as a risk factor for full mutation expansion among Israeli FMR1 premutation carriers.

METHODS: All FMR1 premutation carriers who underwent chorionic villus sampling or amniocentesis at Sheba Medical Center were included in this study. FMR1 PCR assay was performed using the Asuragen Kit in order to determine the number of CGG repeats and AGG interruptions in all women.

RESULTS: 147 FMR1 premutation carriers were included in this study. Among offspring, 66% of all full mutation expansions occurred from maternal alleles with no AGG interruptions. The risk for a full mutation expansion was 15 times higher in premutation alleles with no AGG interruptions compared to 2 AGG interruptions. Moreover, unstable expansions occurred in 78% of alleles with no AGG interruptions whilst this number was reduced to 45% when the allele contained a single AGG interruption, and diminished by 4-fold in 2 AGG-containing alleles.

CONCLUSIONs: The absence of AGG interruptions is a major risk factor for allele instability and full mutation expansion among Israeli FMR1 premutation carriers. Therefore, it is a valuable and fundamental tool and should be part of the genetic and fertility counseling for FMR1 premutation carriers.