Figure 2.

The Loss of Interruption (LOI) Variant Is Associated with an Earlier Age of Onset (AOO) in Individuals with Huntington Disease (HD) and Occurs on Expanded HTT CAG Alleles

(A) The interrupting sequence between the exon one HTT CAG and CCG repeats and representative Sanger electropherograms for the reference sequence and LOI variant are shown. The interrupting sequence is depicted in blue italic font and red nucleotides show point mutations in this region that can result in the LOI variant. The dashed red box indicates the CAG repeat that is measured in diagnostic assays for HD. Nucleotides encoding the glutamine (i.e., CAG/CAA) and proline (i.e., CCG/CCA) tracts are shaded to show that the LOI variant alters the number of contiguous CAG repeats but not the number of glutamine residues in these persons.

(B) The LOI is associated with earlier AOO as determined by the AOO ratio.

(C) LOI carriers present with HD approximately 25 years earlier than predicted on average compared to current models for prediction of AOO. These calculations were performed using data from all HD-LOI subjects as well as mean values for each HD-LOI pedigree, versus HD subjects with the reference interrupting sequence.

(D) Distribution of the HTT CAG repeat lengths in the general population ascertained through genotyping from whole-genome sequencing data. The LOI allele was detected in one research participant and was found on an intermediate allele (indicated with an arrow). Intermediate, reduced penetrance and fully penetrant alleles are shaded.