Abstract
Recent work on Huntington disease (HD) suggests that somatic instability of CAG repeat tracts, which can expand into the hundreds in neurons, explains clinical outcomes better than the length of the inherited allele. Here, we measured somatic expansion in blood samples collected from the same 50 HD mutation carriers over a twenty-year period, along with post-mortem tissue from 15 adults and 7 fetal mutation carriers, to examine somatic expansions at different stages of life. Post-mortem brains, as previously reported, had the greatest expansions, but fetal cortex had virtually none. Somatic instability in blood increased with age, despite blood cells being short-lived compared to neurons, and was driven mostly by CAG repeat length, then by age at sampling and by interaction between these two variables. Expansion rates were higher in symptomatic subjects. These data lend support to a previously proposed computational model of somatic instability-driven disease.
Highlights
Most mutations are stably transmitted from parent to offspring
We calculated an expansion index (EI) based on a specific PCR followed by fragment sizing to identify the peaks corresponding to different numbers of carriers at weeks’ gestation (CAG) repeats, or (CAG)n (Lee et al, 2010; Mouro Pinto et al, 2020)
One might have expected that the high number of mitoses at this stage of brain development would make neural precursors sensitive to double-strand breaks and replication errors (Leija-Salazar et al, 2018; Schwer et al, 2016), but somatic expansions occur through different mechanisms than germline expansions (Khristich and Mirkin, 2020; Tabrizi et al, 2020)
Summary
Most mutations are stably transmitted from parent to offspring This reliable genetic principle does not hold, for dynamic mutation disorders such as Fragile X syndrome or Huntington disease (HD). In these diseases, a sequence such as a CAG repeat tract can expand during transmission, likely through mechanisms involving replication or transcription (Khristich and Mirkin, 2020). On an individual subject basis, we cannot predict the disease course just from the size of the repeat tract: two individuals with the same length repeat expansion in HTT may experience disease onset decades apart (Andrew et al, 1993). The inherited pathological CAG repeat size accounts for about 42–71% of the age at onset in HD (Squitieri et al, 2006), though the confidence limits narrow for tracts longer than 50 CAGs (Andrew et al, 1993; Bates et al, 2015b; Langbehn et al, 2004; Rubinsztein et al, 1997; Wexler et al, 2004)
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