The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions

Christopher C. Dvorak, Elie Haddad, Jennifer Heimall, Elizabeth Dunn, Morton J. Cowan, Sung Yun Pai, Neena Kapoor, Lisa Forbes Satter, Rebecca H. Buckley, Richard J. O'Reilly, Sharat Chandra, Jeffrey J. Bednarski, Olatundun Williams, Ahmad Rayes, Theodore B. Moore, Christen L. Ebens, Blachy J. Davila Saldana, Aleksandra Petrovic, Deepak Chellapandian, Geoffrey D.E. CuvelierMark T. Vander Lugt, Emi H. Caywood, Shanmuganathan Chandrakasan, Hesham Eissa, Frederick D. Goldman, Evan Shereck, Victor M. Aquino, Kenneth B. Desantes, Lisa M. Madden, Holly K. Miller, Lolie Yu, Larisa Broglie, Alfred Gillio, Ami J. Shah, Alan P. Knutsen, Jeffrey P. Andolina, Avni Y. Joshi, Paul Szabolcs, Malika Kapadia, Caridad A. Martinez, Roberta E. Parrot, Kathleen E. Sullivan, Susan E. Prockop, Roshini S. Abraham, Monica S. Thakar, Jennifer W. Leiding, Donald B. Kohn, Michael A. Pulsipher, Linda M. Griffith, Luigi D. Notarangelo, Jennifer M. Puck

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Background: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. Objective: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. Methods: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. Results: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). Conclusions: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.

Original languageEnglish (US)
Pages (from-to)547-555.e5
JournalJournal of Allergy and Clinical Immunology
Issue number2
StatePublished - Feb 2023

Bibliographical note

Funding Information:
The work was supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID); and the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, Md: grant number U54AI082973 (MPI: J.M.P., C.C.D., and E.H.); and grant numbers U54NS064808 and U01TR001263 (PI: J.K.). The Primary Immunodeficiency Treatment Consortium (PIDTC) is a part of the Rare Diseases Clinical Research Network of ORDR, NCATS. The collaborative work of the PIDTC with the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) is supported by the U54 grants listed, along with support of the PTCTC Operations Center by the St. Baldrick’s Foundation and grant number U10HL069254 (PI: M.M.H.). Collaborative work of the PIDTC with the Center for International Blood and Marrow Transplant Research is supported by grant number U24CA076518 (PI: B.E.S.); grant number U01HL069294 (PI: M.M.H.); contract numbers HHSH250201200016C and HHSH234200637015C with the Health Resources and Services Administration , Department of Health and Human Services; and grant numbers N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research . M.J.C. and J.M.P. are supported by the California Institute of Regenerative Medicine (grant no. CLIN2-10830). M.A.P. is supported by grant numbers 1U01AI126612-01A1, P30CA040214, and 2UG1HL069254. S.Y.P. is supported by funding from the Intramural Research Program, NIH, National Cancer Institute , Center for Cancer Research. L.D.N. is supported by the Division of Intramural Research, NIAID, and NIH (grant no. ZIA AI001222-07 to PI L.D.N.).

Publisher Copyright:
© 2022 The Authors


  • leaky/atypical SCID
  • newborn screening
  • Omenn syndrome
  • SCID
  • Severe combined immunodeficiency
  • typical SCID

PubMed: MeSH publication types

  • Journal Article


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