Nezihe Köker Özer1, Ercan Yılmaz2, Erdem Topal2
1Inonu University, Faculty of Medicine, Department of Pediatrics, Malatya Türkiye
2Inonu University, Faculty of Medicine, Pediatric Allergy and Immunology Department, Malatya, Türkiye
Nezihe Köker Özer
10.20411/pai.v11i2.1108
Özer NK, Yılmaz E, Topal E. Diagnostic Certainty in Registry-Based Estimates of Innate and Intrinsic Immunity Defects. Pathogens and Immunity. 2026;11(2):127-129. doi: 10.20411/pai.v11i2.1108
This Letter refers to the article available at doi: 10.20411/pai.v10i2.845
We read with interest the study by Refaat et al describing defects of innate and intrinsic immunity in the Moroccan inborn errors of immunity (IEI) registry [1]. The cohort is particularly valuable because these disorders may remain unrecognized when routine immunological testing is unrevealing. We believe, however, that clarification of diagnostic certainty would strengthen interpretation of the reported frequency and genetic spectrum.
Of 884 patients with IEI, 79 (approximately 9%) were classified as having defects of innate or intrinsic immunity, whereas only 46 (58%) received a genetic diagnosis [1]. The Methods further state that both genetically confirmed patients and those with clinical or biological findings “suggestive of the condition” were included. The operational criteria used to classify the remaining 33 genetically unresolved patients are not provided. This distinction is important because immunoglobulin concentrations and lymphocyte subsets were largely normal in the cohort, and disorders in this category may require pathway-specific functional testing and/or molecular evidence. Without separating confirmed, probable, and possible diagnoses, the reported 9% may represent a mixture of diagnostic certainty levels rather than the frequency of confirmed innate or intrinsic IEI.
Diagnostic certainty also matters within the genetically resolved group. Table 5 lists variants in STAT1, IFNGR1, IFIH1, POLR3A, SNORA31, and other genes, but variant-level ACMG/AMP classification, segregation results, and patient-specific functional evidence are not reported [1]. American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) recommendations incorporate population, computational, functional, and segregation evidence when assigning variant pathogenicity [2].
STAT1 provides a clinically relevant example. In the cohort, STAT1 variants are assigned to both Mendelian susceptibility to mycobacterial disease and chronic mucocutaneous candidiasis [1]. Yet loss-of-function and gain-of-function STAT1 variants produce different biological and clinical phenotypes [3, 4]. This distinction can affect surveillance and treatment, including consideration of JAK inhibition in selected patients with STAT1 gain-of-function disease [4]. Thus, functional direction is not merely descriptive; it can influence clinical management. The 2024 International Union of Immunological Societies (IUIS) classification likewise distinguishes disorders caused by different functional effects of variants within the same gene [5].
We therefore suggest reporting the diagnostic criteria and functional evidence used for the 33 genetically unresolved patients and, for genetically resolved cases, the pathogenicity classification, segregation status, and functional validation of each variant. Stratifying the cohort by diagnostic certainty would preserve the value of this registry while making the 9% estimate more reproducible and clinically interpretable.
The authors acknowledge the use of OpenAI ChatGPT (5.6 Sol) for language editing. AI-assisted text was reviewed, revised, and approved by all authors.
No funding was received for this work.
The authors declare no relevant conflicts of interest.
Submitted August 26, 2026 | Accepted September 14, 2026 | Published October 5, 2026
Copyright © 2026 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License.