A new multisystem ERCC1-hepatorenal syndrome: insights from a clinical cohort, molecular pathogenesis, and management guidelines
Bibliographic record
Abstract
DNA repair disorders are a group of conditions characterized by progressive, multisystem phenotypes. Defining new clinical presentations of these disorders is essential for optimizing patient care. ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair. We sought to define a novel multisystem phenotype associated with biallelic ERCC1 variants and impaired DNA repair. Through international collaboration, we identified seven individuals from five families carrying biallelic ERCC1 variants, including p.Arg156Trp and p.Ala266Pro, who exhibited a distinct clinical phenotype. All individuals presented with growth restriction, photosensitivity, and kidney and liver dysfunction. Notably, three children required liver transplants. Hepatocellular carcinoma developed in four children, resulting in two deaths, including one following treatment with doxorubicin and cisplatin. Older individuals exhibited additional features, including ataxia, basal cell carcinomas, pancreatic insufficiency, ovarian failure, hypothyroidism, and restrictive lung disease. Functional assays using patient-derived fibroblasts demonstrated significant destabilization of the ERCC1-XPF complex and defects in NER and ICL repair. However, residual NER and ICL repair activity was observed, suggesting a hypomorphic effect of the missense variants, which were present either in the homozygous state or in trans with a predicted loss-of-function allele. We define ERCC1-hepatorenal syndrome as a severe, multisystem DNA repair disorder associated with high morbidity and mortality, including a significant risk of pediatric hepatocellular carcinoma. We propose management guidelines emphasizing cancer surveillance and caution with chemotherapy to minimize treatment-related toxicity.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.000 | 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 teacher head, 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".