Bleeding Disorder, Platelet-Type, 18

A number sign (#) is used with this entry because of evidence that platelet-type bleeding disorder-18 (BDPLT18) is caused by homozygous mutation in the RASGRP2 gene (605577) on chromosome 11q13. One such family has been reported.

Clinical Features

Canault et al. (2014) reported 3 sibs, born of consanguineous parents, with a bleeding disorder due to defective platelet function. The patients developed mucocutaneous bleeding around 18 months of age. Features included epistaxis, hematomas, bleeding after tooth extraction, and menorrhagia. Bleeding times were increased, and patient platelets showed reduced aggregation in response to ADP or epinephrine.

Inheritance

The transmission pattern of BDPLT18 in the family reported by Canault et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 sibs, born of consanguineous parents, with a platelet-type bleeding disorder, Canault et al. (2014) identified a homozygous mutation in the RASGRP2 gene (G248W; 605577.0001). The mutation was found by exome sequencing and segregated with the disorder in the family. In vitro functional studies indicated that the mutation caused defective RASGRP2 function, resulting in defective platelet inside-out and outside-in signaling and interfering with platelet aggregation and spreading. The functional deficiencies were confined to platelets and megakaryocytes with no alterations in leukocytes. Platelets from heterozygous carriers showed impaired platelet adhesion under flow conditions in the absence of clinical bleeding, suggesting that partial inhibition of the RASGRP2 catalytic domain could be a therapeutic target to prevent thrombosis.