BRCA1‐associated protein 1: Tumor predisposition syndrome and Kury‐Isidor syndrome, from genotype–phenotype correlation to clinical management

• Published in: Clinical genetics 2024-06, Vol.105 (6), p.589-595
• Main Authors: West, Elizabeth Casey, Chiappetta, Marco, Mattingly, Aubrey Anne, Congedo, Maria Teresa, Evangelista, Jessica, Campanella, Annalisa, Sassorossi, Carolina, Flamini, Sara, Rossi, Teresa, Pistoni, Mariaelena, Abenavoli, Ludovico, Margaritora, Stefano, Lococo, Filippo, Boccuto, Luigi
• Format: Article
• Language: English
• Subjects: Apoptosis; BAP1; BRCA1 protein; BRCA1 Protein - genetics; DNA repair; Female; Genetic Association Studies; Genetic Counseling; Genetic Predisposition to Disease; Genotype & phenotype; Genotypes; genotype–phenotype correlation; Germ-Line Mutation - genetics; Humans; mesothelioma; Neoplastic Syndromes, Hereditary - genetics; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Phenotype; Phenotypes; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumors; Ubiquitin Thiolesterase - genetics
• ISSN: 0009-9163; 1399-0004; 1399-0004
• DOI: 10.1111/cge.14507

The BAP1 tumor suppressor gene encodes a deubiquitinase enzyme involved in several cellular activities, including DNA repair and apoptosis. Germline pathogenic variants in BAP1 have been associated with heritable conditions including BAP1 tumor predisposition syndrome 1 (BAP1‐TPDS1) and a neurodevelopmental disorder known as Kury‐Isidor syndrome (KURIS). Both these conditions are caused by monoallelic, dominant alterations of BAP1 but have never been reported in the same subject or family, suggesting a mutually exclusive genotype–phenotype correlation. This distinction is extremely important considering the early onset and aggressive nature of the types of cancer reported in individuals with TPDS1. Genetic counseling in subjects with germline BAP1 variants is fundamental to predicting the effect of the variant and the expected phenotype, assessing the potential risk of developing cancer for the tested subject and the family members who may carry the same variant and providing the multidisciplinary clinical team with the proper information to establish precise surveillance and management protocols. Kury‐Isidor syndrome and tumor predisposition syndrome 1 are linked to variants of BAP1 which encodes a deubiquitinase enzyme involved in multiple cellular pathways. These variants appear to have a mutually exclusive genotype–phenotype correlation between the two syndromes where missense variants link with Kury‐Isidor and other variants to tumor predisposition syndrome.