An Autosomal Dominant SCID Form Due to a Gain of Function Mutation in the RAC2 Gene

Severe combined immunodeficiencies (SCIDs) form a heterogeneous group of life-threatening genetic disorders defined by the absence of autologous T cells and an intrinsic or extrinsic defect in the B-cell compartment. In our cohort, three newborn patients with bone-marrow hypoplasia associated with clinical and biological features of SCID received allogenic hematopoietic stem cell transplantation in the first weeks of life. To identify the molecular defect involved in this life threatening SCID form, we performed whole-genome sequencing on patient's fibroblasts. The same heterozygous, dominant missense mutation was found in the RAC2gene encoding for the RAC2 GTPase (p.G12R). By biochemical analyses we demonstrated that arginine substitution at position 12 leads to sustained activation of the RAC2 signalling pathway; the G12R mutation is therefore a gain of function mutation. In cord blood hematopoietic cells, we observed that the mutation disrupts mitochondrial activity and blocks hematopoietic stem/progenitor cells (HSPCs) differentiation toward the myeloid and lymphoid lineages. Altogether, our data emphasize the involvement of the RAC2 signalling pathway during hematopoeisis and might thus explain the severity of the patients' clinical and immunological phenotype.

The present study is the first to report an autosomal dominant form of SCID and suggest that RAC2 gene sequencing should be considered for patients with SCID clinical presentation.