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A Large Cohort of RAG1/2-Deficient SCID Patients—Clinical, Immunological, and Prognostic Analysis

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Abstract

Introduction

Severe combined immunodeficiency (SCID) is a fatal disorder resulting from various genetic defects. In the Middle East, where consanguineous marriage is prevalent, autosomal recessive mutations in recombination-activating genes (RAG) are a leading cause of SCID. We present a large cohort of SCID patients due to RAG1 or RAG2 mutations.

Methods

Twenty-six patients with RAG1 or RAG2 deficiency, diagnosed at Sheba Medical Center, were retrospectively investigated. Clinical presentation, immunologic phenotype, genetic analysis, treatment, and outcome were analyzed.

Results

Majority of patients were referred from the Palestinian Authority. Most patients were males of Muslim Arab descent, 77% were born to consanguineous parents, and 65% had family history of immunodeficiency. Nearly all patients suffered from various infections before turning 2 months old, eight patients (31%) presented with Omenn and Omenn-like syndrome, and three patients (11%) had maternal engraftment. Notably, seven patients (27%) suffered from vaccine-derived infections, including a rare case of measles encephalitis. Nineteen patients underwent hematopoietic stem cell transplantation (HSCT) at a median age of 6 months, with a successful outcome for 72% of them. Genetic analysis revealed 11 different mutations (7 RAG2, 4 RAG1), two of them novel.

Conclusions

Consanguineous marriages account for a genetic “founder effect.” SCID is a pediatric emergency that dictates immediate precautions and curative treatment with HSCT. Due to lack of newborn screening for SCID within the Palestinian population, most patients in this cohort were diagnosed upon clinical symptoms, which led to a delayed diagnosis, harmful administration of contra-indicated live vaccines, delay in HSCT, and poor outcome.

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Acknowledgments

We would like to thank the dedicated families of our patients, as well as our Palestinian colleagues. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 755170. We thank the Jeffrey Modell Foundation for their consistent support of our work.

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Correspondence to Noa Greenberg-Kushnir.

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Greenberg-Kushnir, N., Lee, Y.N., Simon, A.J. et al. A Large Cohort of RAG1/2-Deficient SCID Patients—Clinical, Immunological, and Prognostic Analysis. J Clin Immunol 40, 211–222 (2020). https://doi.org/10.1007/s10875-019-00717-1

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