Abstract: The present invention contemplates allele-specific gene editing based on targeting a heterozygous single nucleotide polymorphism (SNP) in a protein coding sequence associated with a genetic disease. The data shown herein demonstrates that the outcome of such gene editing creates a nonesense mutation that results in a marked and selective reduction of mutant protein without affecting wild type protein expression. Expression of a single CRISPR-Cas9 nuclease in neurons generated a high frequency of mutations in the targeted HD allele that included both small insertion/deletion mutations and viral vector insertions. Thus, as disclosed herein, allele-specific targeting of InDel and insertion mutations to heterozygous coding SNPs provides a feasible approach to inactivate autosomal dominant mutations that cause genetic disease.