Successful hematopoietic stem cell transplantation in a patient with a novel mutation in coronin 1A

Abstract

Introduction: Coronin 1A is part of a family of highly conserved actin regulatory proteins with key roles in T cell homeostasis and T cell receptor signaling. Null mutations in coronin 1A result in severe combined immunodeficiency, whereas hypomorphic mutations have been associated with a somewhat milder immunological phenotype. Nevertheless, all patients described so far have markedly reduced naïve peripheral T cells, impaired T cell responses to mitogens, and limited T cell receptor diversity. Interestingly, despite poor thymic output, thymus architecture appears normal. To date, only 2 cases of hematopoietic stem cell transplantation (HSCT) have been reported in coronin 1A deficiency. Aim: To describe the identification, transplantation course, and long term outcome of a Canadian Inuit patient diagnosed with coronin 1A deficiency. Methods: Patient chart review was performed in accordance with institutional research ethics approval. A combination of immunological investigations and molecular genetic analyses were utilized to identify a novel mutation in the tryptophan-aspartate repeat region of coronin 1A. Based on the patient’s profound T cell dysfunction, the decision was made to proceed with HSCT. Results: The patient presented with a history of recurrent urinary tract infections, otitis media, and developmental delay involving poor axial and peripheral muscle tone. Axillary lymphadenopathy was noted and subsequent thymus biopsy revealed aberrant CD7+ T cell deficiency. Lymphocyte responses to mitogens and T cell receptor excision circle levels were markedly reduced, consistent with the diagnosis of severe combined immunodeficiency. Whole exome sequencing and Sanger confirmation revealed a novel mutation in coronin 1A. HSCT using a HLA-matched unrelated donor resulted in long term engraftment and solid immune reconstitution. Conclusion: Very few patients with coronin 1A deficiency have been described to date, making it difficult to evaluate its natural history and management. Here, we describe the presentation, identification, transplantation, and outcome in our patient. Statement of novelty: We describe the successful hematopoietic stem cell transplantation course and outcome in a patient with a novel mutation in coronin 1A.

Novel hemizygous CORO1A variant leads to combined immunodeficiency with defective platelet calcium signaling and cell mobility

“…Since the first patient with this T − B + NK + SCID was identified in 2009, 1 a series of patients with CORO1A protein deficiency have been reported and the disease’s spectrum has been expanded to include a milder phenotype that is caused by hypomorphic CORO1A mutations and leads to T-cell lymphopenia of variable severity, profound defects of naive T-cells, seemingly preserved B- and natural killer (NK) cell compartments, recurrent viral infections, and EBV-associated B-cell lymphoproliferation. 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 …”