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Exploring genetic defects in adults who were clinically diagnosed as severe combined immune deficiency during infancy

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Abstract

Genetic diagnostic tools including whole-exome sequencing (WES) have advanced our understanding in human diseases and become common practice in diagnosing patients with suspected primary immune deficiencies. Establishing a genetic diagnosis is of paramount importance for tailoring adequate therapeutic regimens, including identifying the need for hematopoietic stem cell transplantation (HSCT) and genetic-based therapies. Here, we genetically studied two adult patients who were clinically diagnosed during infancy with severe combined immune deficiency (SCID). Two unrelated patients, both of consanguineous kindred, underwent WES in adulthood, 2 decades after their initial clinical manifestations. Upon clinical presentation, immunological workup was performed, which led to a diagnosis of SCID. The patients presented during infancy with failure to thrive, generalized erythematous rash, and recurrent gastrointestinal and respiratory tract infections, including episodes of Pneumocystis pneumonia infection and Candida albicans fungemia. Hypogammaglobulinemia and T-cell lymphopenia were detected. Both patients were treated with a 10/10 HLA matched sibling donor unconditioned HSCT. Retrospective genetic workup revealed homozygous bi-allelic mutations in IL7RA in one patient and in RAG2 in the other. Our study exemplifies the impact of retrospectively establishing a genetic diagnosis. Pinpointing the genetic cause raises several issues including optimized surveillance and treatment, understanding disease mechanisms and outcomes, future family planning, and social and psychological considerations.

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Acknowledgements

We thank the families for participating in this study. We thank the Jeffrey Modell Foundation, Israel Ministry of Health, and the Israeli Science Foundation for their financial support. Prof. Raz Somech, Dr. Ayal Hendel, and Dr. Yu nee Lee gratefully acknowledge the funding support from the Israeli Science Foundation (ISF) under the Israel Precision Medicine Program (IPMP), grant agreement No. 3115/19.

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Authors and Affiliations

  1. Department of Pediatric Hematology Oncology, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

    Ido Somekh

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ido Somekh, Atar Lev, Yu Nee Lee, Amos J. Simon & Raz Somech

  3. Pediatric Department A and Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel HaShomer, Israel

    Atar Lev, Yu Nee Lee, Amos J. Simon & Raz Somech

  4. The Genomic Unit, Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel

    Ortal Barel

  5. The Mina and Everard Goodman Faculty of Life Sciences, Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel

    Ayal Hendel

  6. Cancer Research Center, Pediatric Immunology Unit, Jeffrey Modell Foundation (JMF) Center, Department of Pediatrics, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, 52621, Tel Hashomer, Israel

    Raz Somech

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  1. Ido Somekh
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Contributions

I.S. and R.S. conceptualized the designed study and drafted the manuscript which was reviewed and approved by all authors. R.S. treated the patients studied. A.L., A.H., Y.N.L., and A.J.S. performed and analyzed immune and genetic experiments. O.B. analyzed WES data.

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Correspondence to Raz Somech.

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Somekh, I., Lev, A., Barel, O. et al. Exploring genetic defects in adults who were clinically diagnosed as severe combined immune deficiency during infancy. Immunol Res 69, 145–152 (2021). https://doi.org/10.1007/s12026-021-09179-3

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