Pulmonary alveolar proteinosis and anemia may be associated with poor prognosis in patients with IARS1 variants
Bibliographic record
Abstract
BACKGROUND: Growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH) is a rare disease caused by compound heterozygous variations in the isoleucyl-tRNA synthetase 1 (IARS1) gene. To date, only a few cases have been reported and there has been no comprehensive analysis of its clinical, pathological, molecular genetic features, or factors associated with a poor prognosis. METHODS: Three new cases of IARS1 deficiency have been documented. A review and summary of the clinical, pathological, and molecular genetic features of previously reported cases was conducted. The prognostic significance of identified risk factors was evaluated using Kaplan-Meier plotter analysis. RESULTS: The 3 new cases harbored 6 novel variants in IARS1. The principal clinical manifestations of IARS1 deficiency were intrauterine growth retardation (13/13), failure to thrive (13/14), feeding difficulties (10/14), elevated aminotransferases (11/14), cholestasis (8/14), acute liver failure (7/14), hepatomegaly (7/14), hypoalbuminemia (10/14), coagulation abnormalities (8/14), microcephaly (11/14), neurodevelopmental delay (10/14), hypotonia (9/14), impaired intellectual development (6/7), recurrent infections (9/14), special facial appearance (8/14), zinc deficiency (4/7), and pulmonary alveolar proteinosis (3/14). The principal pathological features of the liver were fibrosis (6/8), hepatocellular steatosis (5/8), and cholestasis (5/8). A total of 24 variants were identified in 14 cases, comprising a frameshift variant (n = 3), nonsense variant (n = 3), splice variant (n = 2), and missense variant (n = 16). Of the 14 cases, five resulted in death. Kaplan-Meier analysis indicated that the occurrence of pulmonary alveolar proteinosis (HR = 10.837, 95% CI = 1.246-94.257, P = 0.031) and anemia (HR = 15.411, 95%CI = 2.101-113.057, P = 0.007) were associated with a poor prognosis. CONCLUSIONS: In this report, we present three new cases of IARS1 deficiency and provide a comprehensive summary of the clinical, pathological, and molecular genetic characteristics observed in all previously reported cases. Furthermore, our findings suggest that the presence of pulmonary alveolar proteinosis and anemia may be associated with a poor prognosis.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 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".