Purpose In some Huntington disease (HD) patients, the "loss of interruption" (LOI) variant eliminates an interrupting codon in theHTTCAG-repeat tract, which causes earlier age of onset (AOO). The... Show morePurpose In some Huntington disease (HD) patients, the "loss of interruption" (LOI) variant eliminates an interrupting codon in theHTTCAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the variant also causes CAG size misestimation. We developed a rapid LOI detection screen, enabling unbiased frequency estimation among manifest HD patients. Additionally, we combined published data with clinical data from newly identified patients to accurately characterize the LOI's effect on AOO. Methods We developed a LOI detection polymerase chain reaction (PCR) assay, and screened patients to estimate the frequency of the LOI variant and its effect on AOO. Results Mean onset for LOI carriers (n = 49) is 20.4 years earlier than expected based on diagnosed CAG size. After correcting for CAG size underestimation, the variant is still associated with onset 9.5 years earlier. The LOI is present in 1.02% of symptomatic HD patients, and in 32.2% of symptomatic reduced penetrance (RP) range patients (36-39 CAGs). Conclusion The LOI causes significantly earlier onset, greater than expected by CAG length, particularly in persons with 36-39 CAG repeats. Detection of this variant has implications for HD families, especially for those in the RP range. Show less
