Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset condition characterised by cerebellar ataxia and intention tremor, usually found in individuals with FMR1 premutation alleles (PM—CGG expansion of 55–199 repeats). Population studies estimate that between 1 in 250 and 1 in 1600 men have a PM, with up to 45% of these men suggested to develop FXTAS by age 80. We used a Bayesian approach to compare the probability of finding a specific PM genotype in an ataxia population to a population control group and found an estimated penetrance of <1% (0.031%; CI 0.007% to 0.141%) for men with ≤70 CGGs. These findings suggest that men with a PM of ≤70 CGGs, who comprise the vast majority of those with a PM, have a much lower risk of being affected with FXTAS than previously suggested. This is an issue of growing importance for accurate genetic counselling, as those with a PM of ≤70 CGGs are increasingly detected through community carrier screening or neurodevelopmental assessment programmes.
- DNA repeat expansion
- human genetics
- neurodegenerative diseases
- genetic counseling
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Contributors EM and MF formulated the presented idea. EM performed the literature review and collation of data. ZY performed data analysis and computation. EM wrote the inital manuscript with support from MF. CK, DG and KK reviewed the initial manuscript critically and provided important intellectual content. All authors discussed the results and contributed to the final manuscript.
Funding KRK receives funding from the Paul Ainsworth Family Foundation, the Michael J. Fox Foundation, Aligning Science Across Parkinson’s (ASAP) initiative and honorarium from Seqirus Australia. CMK is funded by a National Health and Medical Research Council Early Career fellowship (1120561). DEG is funded by the Medical Research Future Fund (MRF1141334).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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