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. © 2021 International Parkinson and Movement Disorder Society.