Age of Onset of Huntington's Disease in Carriers of Reduced Penetrance Alleles

Background Age of manifest Huntington's disease (HD) onset correlates with number of CAG repeats in the huntingtin gene. Little is known about onset with 36 to 39 repeats, the reduced penetrance (RP) range. Objectives We provide allele-specific estimates of HD penetrance (diagnostic confidence level of 4) for RP allele carriers. Methods We analyzed 431 pre-manifest RP allele carriers from Enroll-HD, the largest prospective observational HD study. Cumulative penetrance (CP) was estimated from Kaplan-Meier curves. Results No one with 36 repeats (n = 25) phenoconverted. CP for 38 repeats (n = 120) was 32% (95% confidence interval [CI] 0%-55%) and 51% (CI, 10%-73%) by ages 70 and 75, respectively, and 68% (CI, 46%-81%) and 81% (CI, 58%-92%) by ages 70 and 75 for 39 repeats (n = 253). CP was not estimable at those ages for 37 repeats (n = 33). Conclusions Differences by RP-range repeat length did not reach significance with a 3-year median follow-up duration among censored individuals. (c) 2021 International Parkinson and Movement Disorder Society

Automated summary

This study provides allele-specific estimates of HD penetrance for RP allele carriers with different CAG repeat lengths, with 37 repeats being unestimable. Although there were differences by RP-range repeat length, they did not reach significance during the 3-year median follow-up duration among censored individuals.