Third reported patient with RAP1B‐related syndromic thrombocytopenia and novel clinical findings

Abstract

RAP1B is a RAS-superfamily small GTP-binding protein involved in numerous cell processes. Pathogenic gain-of-function variants in this gene have been associated with RAP1B-related syndromic thrombocytopenia, an ultrarare disorder characterized by hematologic abnormalities, neurodevelopmental delays, growth delay, and congenital birth defects including cardiovascular, genitourinary, neurologic, and skeletal systems. We report a 23-year-old male with a novel, de novo RAP1B gain-of-function variant identified on genome sequencing. This is the third reported case which expands the molecular and phenotypic spectrum of RAP1B-related syndromic thrombocytopenia.

Optical genome mapping identifies structural variants in potentially new cancer predisposition candidate genes in pediatric cancer patients

“…23,24 Activating missense variants in RAP1B have been described in three patients with syndromic thrombocytopenia and multiple malformations, including microcephaly and learning difficulties. 25,26 In line with these findings, P10 had mild global developmental delay and a growth disorder in addition to his B-ALL. However, the analysis of RAP1B mRNA expression in the PBMCs of the patient revealed no altered expression in comparison to the father or the controls (Figure S3C).…”

“…RAP1B encodes for a protein of the RAS family of small GTP binding proteins with mitogenic and oncogenic properties 23,24 . Activating missense variants in RAP1B have been described in three patients with syndromic thrombocytopenia and multiple malformations, including microcephaly and learning difficulties 25,26 . In line with these findings, P10 had mild global developmental delay and a growth disorder in addition to his B‐ALL.…”

Adding to the evidence of gene‐disease association of RAP1B and syndromic thrombocytopenia

“…A de novo NM_001010942.2( RAP1B ):c.451A>G, p.(Lys151Glu) variant was identified in an individual with a Kabuki‐like phenotype, without reported haematological abnormalities, 5 and more recently, de novo RAP1B variants were identified in individuals with congenital thrombocytopenia, intellectual disability and congenital malformations 6,7 . Specifically, three de novo missense variants, NM_001010942.2( RAP1B ):c.35G>T, (p.(Gly12Val), 6 NM_001010942.2( RAP1B ):c.178G>C, p.(Gly60Arg) 6 and NM_001010942.2( RAP1B ):c.176C>G, p.(Ala59Gly) 7 were identified in three independent cases of syndromic thrombocytopenia. Other features were more heterogeneous 6,7 …”

“…Specifically, three de novo missense variants, NM_001010942.2( RAP1B ):c.35G>T, (p.(Gly12Val), 6 NM_001010942.2( RAP1B ):c.178G>C, p.(Gly60Arg) 6 and NM_001010942.2( RAP1B ):c.176C>G, p.(Ala59Gly) 7 were identified in three independent cases of syndromic thrombocytopenia. Other features were more heterogeneous 6,7 …”

“…Other features were more heterogeneous. 6,7 The Clinical Genome Resource (ClinGen) 8 classifies the genedisease association evidence between RAP1B and syndromic constitutional thrombocytopenia as limited, 8 while there is no OMIM entry for this phenotype and RAP1B. In order to assess the evidence for a causative role of RAP1B variants in thrombocytopenia, we searched our Biodatabank for heterozygous variants in RAP1B and identified two individuals featuring thrombocytopenia and other syndromic features.…”