Using the method of saturation genome editing (SGE), researchers have assessed the functional impact of 99% of all possible single nucleotide variants in the coding sequence of the BAP1 gene. SGE is a technique that uses CRISPR/Cas genome editing to produce cells that each carry one of all theoretically possible variants of a particular gene. The cells are then tested for their fitness and for each variant a functional score is determined to help evaluate whether individual variants will indeed cause disease.

BAP1 is a tumor suppressor gene and encodes BRCA1-associated protein 1, a deubiquitinase involved in the control of essential cellular processes like cell proliferation and differentiation, transcription, and DNA repair. Somatic mutations in BAP1 have been described in a variety of very aggressive tumors. Germline mutations in BAP1 cause a hereditary tumor predisposition syndrome and, interestingly, have also been linked to a neurodevelopmental disorder.

The authors of the study published in Nature Genetics also performed association studies using databases as for example the UK Biobank. They found that variants identified by them as disruptive were associated significantly with increased frequency of cancer and, independently, with higher levels of the circulating growth factor IGF-1. These results may suggest a potential pathomechanism and a target for a future approach to treat BAP1-associated conditions.