Whole exome sequencing identifies causative compound heterozygous variants in <i>PRF1</i> in late-onset familial hemophagocytic lymphohistiocytosis
Bibliographic record
Abstract
Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disease in which cells of the immune system are overactivated, leading to uncontrolled inflammation and tissue destruction. Inherited or familial forms of HLH (FHL) are further classified into FHL1 to 5, based on the underlying genetic etiology. The most common form, FHL2, is associated with mutations in the PRF1 gene encoding perforin, a pore-forming glycoprotein required for natural killer and cytotoxic T cell-mediated apoptosis. Importantly, diagnosis of FHL can be challenging, particularly in late-onset cases in which presentation is delayed beyond the first years of life. Aim: We report the essential role of whole exome sequencing in the diagnostic work-up of a patient with complex, late-onset FHL. Methods: A comprehensive retrospective chart review was performed. Results: Our patient presented at 11 years of age with recurrent fever, hepatosplenomegaly, and pancytopenia. In the following years, she was admitted to hospital on multiple occasions, including twice for febrile neutropenia, and once for febrile cytopenia. Serial immune evaluation revealed features of immune dysregulation. While HLH was suspected, she did not fulfil the diagnostic criteria. Initial genetic work-up involving a targeted primary immunodeficiency gene panel identified only a single novel variant of uncertain significance, c.T374C (p.I125T) in PRF1. Subsequently, research-based whole exome sequencing was performed which revealed a second variant, c.C272T (p.A91V), in the same gene. The expanded genetic findings, a set of compound heterozygous missense mutations in PRF1, strengthened the diagnosis of FHL. She later fulfilled the diagnostic criteria for HLH. Conclusion: Whole exome sequencing identified compound heterozygous mutations in the PRF1 gene in a patient with late-onset FHL. Statement of Novelty: We report the use of whole exome sequencing to identify compound heterozygous mutations in PRF1, including a novel p.I125T variant not previously identified in FHL.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".