RAP1B

Inheritance Pattern: AD

Disease ID:MONDO:0958000

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0958000

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0958000

Submitter: ClinGen

*RAP1B* was first associated with autosomal dominant syndromic thrombocytopenia in 2020 (Niemann JH, et al., 2020, PMID: 32627184). Six probands in 3 publications (PMID: 32627184, 35451551, 37850357, SCV006101064.1) 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). *RAP1B* functions as a molecular switch in integrin-mediated signaling pathways, cycling between inactive GDP-bound and active GTP-bound states. Upon activation, *RAP1B* promotes talin recruitment to integrin β3, facilitating integrin αIIbβ3 activation, which is essential for platelet aggregation and immune cell adhesion (PMID: 31484765). This biochemical role aligns with the observed disease mechanisms in patients with RAP1B gain-of-function variants. The inappropriate activation of integrin-mediated signaling cascades due to these variants thus underlies the pathogenic mechanisms linking RAP1B GOF mutations to hematologic and immunologic disease phenotypes (PMID: 39225097). This gene-disease pair was originally evaluated by the Hemostasis/Thrombosis GCEP on 2022 Sep 28. It was re-evaluated on 2025 Oct 28. As a result of this reevaluation, the classification increased from Limted to Moderate with the addition of three new probands (PMID: 37850357, SCV006101064.1) and functional alteration evidence (PMID: 39225097). 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.

Inheritance Pattern: AD

Disease ID:MONDO:0958000

Submitter: Ambry Genetics