Repeat-expansion diseases, such as Huntington’s disease, often cause detrimental neurodegenerative phenotypes and can be intractable. The onset of Huntington’s disease is dictated by the inherited CAG repeat length and the disease is driven by further somatic repeat expansion in the brain. Although cellular and genome-wide association studies (GWAS) have identified mismatch repair (MMR) genes, and other DNA repair or replication genes, as modifiers of the disease, the field lacks an efficient in vivo system to systematically screen and validate candidate genes.

To address this technical limitation and establish a high-throughput screening tool, Mouro Pinto et al. establish a CRISPR–Cas9-based system in HttQ111 knock-in mice, by delivery of adeno-associated virus (AAV) in the liver. They validate this screening platform against known repeat-expansion modifiers, observing similar phenotypes to those in constitutive knockout alleles. They then screen genes involved in repeat instability, including genes implicated in other repeat-expansion disorders, DNA repair and replication factors, as well as candidates identified in GWAS screens. Among the expansion-promoting factors, the involvement of all four subunits of DNA polymerase δ (POLδ) and the implication of genes involved in transcription-coupled repair is notable, and among the suppressors, the identification of HMGB1, a protein implicated in binding slipped repeats, is intriguing.