Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a toxic gain-of-function CAG expansion in the first exon of the huntingtin () gene. The monogenic nature of HD makes mutant () inactivation a promising therapeutic strategy. Single nucleotide polymorphisms frequently associated with CAG expansion have been explored to selectively inactivate allele using the CRISPR/Cas9 system. One of such allele-selective approaches consists of excising a region flanking the first exon of by inducing simultaneous double-strand breaks at upstream and downstream positions of the exon 1. The removal of the first exon of deletes the CAG expansion and important transcription regulatory sites, leading to inactivation. However, the frequency of deletion events is yet to be quantified either or . Here, we developed accurate quantitative digital polymerase chain reaction-based assays to assess exon 1 deletion and in fully humanized HU97/18 mice. Our results demonstrate that dual-single guide RNA (sgRNA) strategies are efficient and that 67% of HTT editing events are leading to exon 1 deletion in HEK293T cells. In contrast, these sgRNA actively cleaved in HU97/18 mice, but most editing events do not lead to exon 1 deletion (10% exon 1 deletion). We also showed that the editing pattern is not affected by CAG expansion but may potentially be due to the presence of multiple copies of wildtype genes HU97/18 mice as well as the slow kinetics of AAV-mediated CRISPR/Cas9 delivery.