Clinical and Genetic Characteristics of Global Cohort of 132 Individuals with Janus Kinase-3 Deficiency
Bibliographic record
Abstract
Background and Aims Janus kinase-3 (JAK3) deficiency, first described in 1995, is an autosomal recessive inborn error of immunity that mostly results in variants of severe combined immunodeficiency (SCID). The frequency is estimated to account for 7-14% of heritable SCID, with sporadic cases in the Western world. Neither preferential “hot spots” nor founder effects have yet been documented. Hereby, we aim to describe the global experience of JAK3-related diseases regarding clinical spectrum, genetic landscape, including founder variants and treatment strategies. Methods We extracted clinical, genetic, and immunological data from published cases on patients with СID/SCID phenotype caused by defects in the JAK3 gene. The literature search included unpublished cases from collaborators, reports from meetings of the European Society for Immunodeficiencies (ESID), of the Clinical Immunology Society (CIS), and published data in the biomedical research search engine (PubMed) from 1995 to 2024. Results Our cohort includes 132 patients with 47 unique genetic defects, including 35 novel variants (18 homozygous, 17 heterozygous). The patients were from 5 continents with majority of Asian ancestry. Country of diagnosis included North America (USA [n = 42]); South America (Brazil [n = 3]); Europe (Turkey [n = 8], Hungary [n = 1], Poland [n = 6], UK [n = 5], Italy [n = 5], Israel [n = 4], Belarus [n = 4], Russian Federation [n = 3], Georgia [n = 3], Spain [n = 1], Germany [n = 1]); Asia (India [n = 16], Iran [n = 6],China [n = 4], Pakistan [n = 1], Japan [n = 1]); and Africa (Egypt [n = 16], Saudi Arabia [n = 1], Sudan [n = 1]). Forty-five (35%) of patients from the cohort were born to consanguineous parents in 31 families from Georgia (n = 3, 1-family), Russian Federation (n = 3/2-family), Sudan (n = 1), Turkey (n = 8, 5-family), Israel (n = 4, 2-family), India (n = 3, 2-family), Egypt(n = 13, 8-family), UK (n = 5, 4-family), China (n = 1), Brazil (n = 1), Spain (n = 1), Italy (n = 1), Pakistan (n = 1), and Saudi (n = 1). 13 novel founder variants are identified. The same founder variant was seen in several countries. The majority of genetic defects were homozygous (68%); 40/132 compound were heterozygous, and 2 patients had germline heterozygous gain-of-function. The variants occurred across the entire JAK3 gene with no hotspots. Only 6 (5%) of 132 cases developed Omenn syndrome. 61 patients were transplanted, 17 died at the age of 9 months (mean age 9-18 months), and 44 are alive. Conclusions We describe for the first time a global cohort of JAK3 with 132 patients with founder effects in a subgroup. Patients were identified in four continents but are most common in countries with a high rate of consanguinity. Founder effect was identified in 14 regions.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".