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Saturation genome editing of BAP1 functionally classifies somatic and germline variants. | LitMetric

AI Article Synopsis

  • Researchers conducted comprehensive genome editing on the BAP1 gene, which is related to tumors and neurodevelopmental issues, to study rare genetic variants.
  • They identified over 18,000 unique variants, with more than 6,000 showing abnormal functions, and linked their findings to health data from the UK Biobank and various cancer collections.
  • The study revealed that certain harmful BAP1 variants are connected to higher levels of the IGF-1 protein, highlighting a potential target for therapy, and they developed a highly accurate tool for interpreting genetic variants.

Article Abstract

Many variants that we inherit from our parents or acquire de novo or somatically are rare, limiting the precision with which we can associate them with disease. We performed exhaustive saturation genome editing (SGE) of BAP1, the disruption of which is linked to tumorigenesis and altered neurodevelopment. We experimentally characterized 18,108 unique variants, of which 6,196 were found to have abnormal functions, and then used these data to evaluate phenotypic associations in the UK Biobank. We also characterized variants in a large population-ascertained tumor collection, in cancer pedigrees and ClinVar, and explored the behavior of cancer-associated variants compared to that of variants linked to neurodevelopmental phenotypes. Our analyses demonstrated that disruptive germline BAP1 variants were significantly associated with higher circulating levels of the mitogen IGF-1, suggesting a possible pathological mechanism and therapeutic target. Furthermore, we built a variant classifier with >98% sensitivity and specificity and quantify evidence strengths to aid precision variant interpretation.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250367PMC
http://dx.doi.org/10.1038/s41588-024-01799-3DOI Listing

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