Wellcome Sanger Institute, Hinxton, UK.
Metabolic Research Laboratory, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Nat Genet. 2024 Jul;56(7):1434-1445. doi: 10.1038/s41588-024-01799-3. Epub 2024 Jul 5.
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.
我们从父母那里遗传或新获得的许多变体或体细胞变体都是罕见的，这限制了我们将它们与疾病相关联的精确性。我们对 BAP1 进行了详尽的饱和基因组编辑（SGE），BAP1 的破坏与肿瘤发生和神经发育改变有关。我们对 18,108 个独特的变体进行了实验特征分析，其中 6,196 个变体被发现具有异常功能，然后使用这些数据在英国生物银行中评估表型相关性。我们还对大型人群确定的肿瘤收集、癌症家系和 ClinVar 中的变体进行了特征分析，并探讨了癌症相关变体与神经发育表型相关变体的行为。我们的分析表明，破坏性的种系 BAP1 变体与循环中更高水平的有丝分裂原 IGF-1 显著相关，这表明存在可能的病理机制和治疗靶点。此外，我们构建了一个具有>98%敏感性和特异性的变体分类器，并量化证据强度以帮助精确变体解释。
