Syndromic thrombocytopenia encompasses a heterogeneous group of disorders characterized by both quantitative and qualitative defects of platelets, often accompanied by other malformations. The clinical manifestations of patients vary in severity, but bleeding is considered the main complication, which can lead to the development of other disorders such as hematological malignancies. Recently, heterozygous, de novo variants in RAP1B have been reported in five cases of syndromic thrombocytopenia. Here, we report an additional case of syndromic thrombocytopenia associated with a rare de novo variant in RAP1B.

We present a case of a 2-year-old female patient with thrombocytopenia first observed at the age of 6 months. She has severe, persistent thrombocytopenia that is refractory to various therapies. The main phenotypic characteristics identified were hypertelorism, low ear implantation, and a broad forehead. Exome sequencing revealed a rare de novo heterozygous variant in the RAP1B gene (NM_001010942.3 c.178G>A p. (Gly60Arg)), classified as likely pathogenic.

The RAP1B gene (OMIM: 179530) is associated with the clinical phenotype of syndromic constitutional thrombocytopenia. Currently, only a few genotype-phenotype associations have been described in the literature. The previously reported variants include c.35G>T (p.Gly12Val), c.176C>G (p.Ala59Gly), c.178G>C (p.Gly60Arg), c.35G>A (p.Gly12Glu), and c.178G>A (p.Gly60Arg). RAP1B is a member of the RAS superfamily of small GTPases involved in many cellular processes. Previous studies have shown a link between RAP1B activation and platelet function in humans and mice. Our case report shares the common phenotype of thrombocytopenia (HP: 0001873), suggesting the clinical relevance of this phenotype to variants in this region of the RAP1B gene. Notably, 4 out of 5 (80%) described variants in public genomic databases are located in exon 4, indicating that this exon may be particularly relevant to the clinical condition.

Our data support that the RAP1B variant detected in our patient may contribute to the phenotype through dysregulation of the MEK/ERK pathway. The effects of variants in RAP1B explain the divergent phenotypes observed among patients. Nonetheless, further studies are required to understand better the correlation between genotype and phenotype.