Significant underascertainment in Huntington’s disease

While Huntington's disease (HD), a Mendelian disorder caused by an expanded CAG repeat in <i>HTT</i>, is considered rare, the true prevalence could be significantly higher due to substantial underascertainment. Given inherent biases in empirically assessing disease prevalence, we performed mathematical modelling and validation analyses to estimate the frequency of expanded CAG repeats in the general population to better understand the disease prevalence. We developed an exponential decay model after confirming that the logarithmic decrease in frequency of CAG repeats extends into the pathogenic range (CAG > 35). The model was further refined by incorporating HD onset and mortality probabilities to estimate the clinical ascertainment rate. Our age-adjusted exponential decay model estimated one expanded repeat in 325 people and further showed that the frequency of expanded repeats decreases with age due to the early mortality associated with HD, which was validated by All of Us and UK Biobank data. Importantly, our data suggest that approximately half of symptomatic HD individuals aged 30-70 are not clinically ascertained/diagnosed. Our data, showing higher frequencies of expanded repeats in the general population and significant underascertainment rates, imply that HD prevalence could be twice as high as current estimates.