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Somatic RAP1B gain-of-function variant underlies isolated thrombocytopenia and immunodeficiency.

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Gain-of-function variants in Ras-related protein 1B (RAP1B) cause combined immunodeficiency and thrombocytopenia. A novel RAP1B variant in a patient led to severe hematological issues, resolved by stem cell transplantation.

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Area of Science:

  • Molecular biology
  • Immunology
  • Hematology

Background:

  • Ras-related protein 1B (RAP1B) is a small GTPase regulating cell signaling and integrin activation.
  • Germline RAP1B variants are linked to syndromic thrombocytopenia, but their impact is unclear.

Purpose of the Study:

  • To investigate the causality and pathophysiology of RAP1B variants in a patient with neonatal thrombocytopenia and combined immunodeficiency.
  • To characterize the functional impact of a novel RAP1B variant (p.G12E).

Main Methods:

  • Genetic sequencing to identify RAP1B variants.
  • Functional assays to assess RAP1B activation, talin recruitment, and integrin activation.
  • Analysis of variant allele frequency in different immune cell compartments.
  • Evaluation of treatment outcomes following allogeneic hematopoietic stem cell transplantation.

Main Results:

  • A heterozygous de novo RAP1B variant (p.G12E) was identified in a patient with neonatal thrombocytopenia, combined immunodeficiency, neutropenia, and monocytopenia.
  • The p.G12E variant, along with previously reported variants (p.G12V, p.G60R), demonstrated gain-of-function activity, increasing RAP1B activation and downstream integrin signaling.
  • The p.G12E variant exhibited somatic mosaicism, with differential allele frequencies in peripheral blood and bone marrow.
  • Allogeneic hematopoietic stem cell transplantation successfully corrected the patient's hemato-immunological phenotype.

Conclusions:

  • Monoallelic gain-of-function RAP1B variants are a cause of constitutive immunodeficiency and thrombocytopenia.
  • The phenotypic spectrum of RAP1B variants ranges from isolated hematological issues to complex syndromic features.
  • Somatic mosaicism of RAP1B variants can influence disease presentation and progression.