Submission Details

RAP1B was first associated with autosomal dominant syndromic thrombocytopenia in 2020 (Niemann JH, et al., 2020, PMID: 32627184). Three probands in 2 publications (PMID: 32627184, 35451551) have been reported with predicted gain-of-function missense variants. Common features among these patients include thrombocytopenia with leucopenia and lymphopenia, mild intellectual disability with or without learning disability, congenital brain malformations, and dysmorphic features. Experimentally, this gene-disease relationship is supported by the fact that, while Rap1 proteins are ubiquitously expressed in tissues, RAP1B is the predominant Rap1 isoform and the most abundant Ras family member in platelets (PMID: 1628649). Additionally, a null mouse model found that mice did not recapitulate the syndromic thrombocytopenia observed in patients but did draw a connection between Rap1b and normal platelet function (PMID: 15696195). In summary, there is limited evidence to support this gene-disease association. While more evidence is needed to establish this association definitively, no convincing contradictory evidence has emerged. Of note, laboratory studies on RAP1 germline loss-of-function variants (RAP1A p.Arg163Thr, RAP1B p.Lys151Glu) have shown that these variants cause dysregulation of the MAPK pathway and manifest as Kabuki-like syndrome (KL-S) with features including short stature, microcephaly, facial dysmorphism, developmental delay, and seizures. Although there are some overlap with the clinical features in these patients, there is a difference in mechanism and thrombocytopenia was not part of the clinical features of KL-S (Bogershausen et al., 2015) so this is considered a separate disease entity.