Absence of AGG Interruptions Is a Risk Factor for Full Mutation Expansion Among Israeli FMR1 Premutation Carriers

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Fragile X syndrome (FXS) is a common X-linked intellectual disability.
• FXS results from expansions of CGG repeats in the FMR1 gene.
• AGG interruptions within CGG repeats act as protective factors against expansion.

Purpose of the Study:

• To validate the relevance of AGG analysis for risk assessment in the Israeli population.
• To combine data with New York State Institute for Basic Research in Developmental Disabilities (IBR) for a larger, diverse cohort.
• To examine risks of unstable transmissions and full mutation expansions among FMR1 premutation carriers.

Main Methods:

• Analysis of 1471 maternal transmissions of FMR1 premutation alleles.
• Correlation of AGG interruption numbers with transmission stability and full mutation expansion.
• Combined data from Israeli and New York populations for a comprehensive ethnic analysis.

Main Results:

• 74.9% of transmissions were unstable, with 20.6% resulting in full mutation expansions.
• Alleles with no AGG interruptions showed 97.4% instability and 40% full mutation expansion.
• Alleles with 2 or more AGGs had significantly lower instability (46.7%) and full mutation expansion (3.2%), with none observed for 3+ AGGs.

Conclusions:

• AGG interruptions are crucial for accurate risk assessment in FMR1 premutation carriers.
• Risk estimates should incorporate both CGG repeat size and AGG interruption number.
• Findings are relevant for carrier screening and genetic counseling in Israel and globally.