Study of the Functionality of New Genetic Variants at the Origin of Constitutional Platelet Disease.

Platelets are circulating blood cells. They bind to each other and to the wall of the damaged vessel to prevent excessive blood loss.

Platelets can be :

• insufficient in number in the case of thrombocytopenia;
• or non-functional in the case of thrombopathy. Constitutional thrombopathies and thrombopenias are rare diseases. Constitutional thrombopenias cause haemorrhage of variable intensity and are sometimes a sign of more serious haematological pathologies. The evolutionary risk of some constitutional thrombopenias is the appearance of myelofibrosis, dysmyelopoiesis or malignant proliferation. While the evolutionary stakes of some thrombopenias and especially syndromic thrombopenias will be more likely to affect other organs (kidney, heart, bones, brain, ...), other constitutional thrombopenias will have few consequences. Their diagnosis will then have the major challenge of distinguishing them from immunological thrombopenias and avoiding the use of inappropriate and sometimes severe treatments (corticosteroids, IV immunoglobulins, immunosuppressants, splenectomy). Mutations in more than forty genes have been identified to date and are responsible for thrombocytopenia.

Constitutional thrombopathies are heterogeneous and may involve different platelet constituents. In short, when platelets are stimulated at a lesion site, various soluble or matrix agonists bind to platelet receptors to induce calcium flow, secretion and platelet aggregation at a vascular gap to prevent blood loss. Constitutional thrombopathies are primarily at risk of spontaneous or induced mucocutaneous bleeding. Some thrombopathies are also part of more complex syndromic patterns. In recent decades, considerable progress has been made in the understanding of thrombopathies, enabling them to be better identified. Details have been provided on platelet dysfunctions linked to abnormalities in the processes of granule biogenesis and secretion, and to signalling defects (in particular surface receptor deficiency). Currently, more than thirty genes are the site of autosomal dominant, recessive or X-linked mutations and can be sequenced.

A national organisation has been set up for the molecular diagnosis of these pathologies. DNA samples from patients meeting strict criteria (familial nature, chronic pathology, associated signs) are sent to the molecular biology departments. A panel of 80 genes is then sequenced in order to identify genetic variations potentially responsible for the pathology. In 40% of cases, a diagnosis of certainty will be made. For the remaining 60%, the analysis will remain non-informative for several reasons: