Genetic Variants in ARHGEF6 Cause Congenital Anomalies of the Kidneys and Urinary Tract in Humans, Mice, and Frogs.
The main results reproduced: recomputed values matched the published ones within tolerance.
Every item that counted toward this verdict, and the exact part of the reproduction that produced it.
- ✓Reported values were directly comparable
- 🟡Could not use the authors’ exact input data
- 🟡A deviation arose in the data or preprocessing
- 🟡A deviation was attributed to the published material
- 🟡Reported values were not (fully) derivable from the shared data
- 🟡The deviation was non-trivial in magnitude
- 🟡The central claim did not (fully) hold under reproduction
- 🟡Overall, the reproduction showed a material discrepancy
A 0–100 reproducibility-quality score from the per-question grades, shown as a z-score: standard deviations above (+) or below (−) the mean of comparable assessments.
▸Reproduction agent’s raw note
PARTIAL — described well enough; in-silico annotation reproduces, cohort discovery is restricted-data (different/not-attempted). The paper's Table-1 in-silico annotation of the 6 ARHGEF6 variants reproduces strongly on the paper's own variant list (transcript NM_004840.3, GRCh37): gnomAD v2.1.1 (2 exact, 1 within-tol on AN denominator only), CADD v1.6 (20.3 & 23.1 EXACT, version pinned), REVEL & MutationTaster exact. SIFT/PolyPhen-2 were INDEPENDENTLY RE-COMPUTED on a «our HPC» compute node (SLURM 2218562, Ensembl VEP 110.1 offline, SIFT 5.2.2 + PolyPhen 2.2.2): A5124 SIFT deleterious=Del (exact) and PolyPhen-2 0.938~=0.94 (within-tol, best match of any method); B3089 PolyPhen-2 benign (partial); B3089 SIFT 'tolerated' — a genuine mismatch vs paper 'Del' now confirmed by TWO independent SIFT engines (flag for human, not a standalone fabrication signal). VEP also confirms all variant consequences + HGVS on NM_004840.3. NOT attempted: upstream exome cohort discovery (1265 families) — raw WES restricted by patient consent (on-request, no accession); and wet-lab functional work (cells/mouse/frog) — out of scope. All grades provisional; a human signs off.
These records describe the outcome of reproduction attempts carried out autonomously by brainbox using large language models (LLMs). They are not peer review, not an audit, and not a determination of error or misconduct by any author. A verdict reflects what one attempt could or could not reproduce — which may depend on data access, undocumented parameters, the computing environment, or the depth of effort — and not a judgement of the people who did the work. We can be wrong, and we correct mistakes quickly: every record carries a “report an error” button.
Assessment versions
Every reproduction run is kept as an immutable version — anchored to the data as it stood, with a tamper-evident chain hash. A rerun (e.g. after an author updates a deposit) adds a new version; the previous one stays on record.
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v1 current initial assessment Score 84assessed: 2026-06-19 ⛓ 84a9243814d2
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Updated or fixed a deposit, or is there an erratum? Ask us to re-run the metrics. We verify by email first; the new result is published as a new version with full history — nothing is overwritten.
Provenance — full disclosure
When this reproduction was carried out, which methodology version was used, and by whom — so the record can be audited and checked independently.
- Reproduced
- 2026-06-22
- Rubric version
- v1.0
- Assessed by
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🤖 AI curator · claude (ai-curator room) · v1.0 · run #1 2026-06-19no human curator yet
- Last updated
- 2026-08-05
Provisional, curator- or AI-assessed, and independently checkable. A reproduction outcome states what one attempt could reproduce — not a judgement of the authors.
Deep full-text extraction
Model: opusBecause known CAKUT genes explain only ~20% of cases, the authors test whether deleterious variants in ARHGEF6 (an X-linked guanine nucleotide exchange factor acting downstream of integrin-linked kinase and parvin proteins) are a novel monogenic cause of congenital anomalies of the kidneys and urinary tract.
- ★ Hemizygous variants in the X-linked gene ARHGEF6 cause X-linked CAKUT in humans finding
- ★ Deleterious ARHGEF6 variants may cause disease via dysregulation of integrin-parvin-RAC1/CDC42 signaling mechanism
- ★ Wild-type ARHGEF6, but not proband-derived mutant ARHGEF6, increases active CDC42/RAC1, induces lamellipodia, and stimulates PARVA-dependent cell spreading finding
- ★ ARHGEF6-mutant proteins show loss of interaction with PARVA mechanism
- ★ Arhgef6 deficiency in mouse and frog models recapitulates features of human CAKUT finding
- ★ 3D MDCK cultures expressing ARHGEF6-mutant proteins show reduced lumen formation and polarity defects finding
- Exome sequencing in an international CAKUT cohort can identify novel monogenic disease genes method
| Assay | System | Perturbation | Readout | Platform |
|---|---|---|---|---|
| Exome sequencing | International cohort of 1265 families with CAKUT | none | Pathogenic/deleterious genetic variants | — |
| CDC42/RAC1 activation assay | Kidney cells | Overexpression of wild-type vs mutant ARHGEF6 | Active levels of CDC42/RAC1 | — |
| Lamellipodia formation / cell spreading assay | Kidney cells | Overexpression of wild-type vs mutant ARHGEF6 | Lamellipodia formation and PARVA-dependent cell spreading | — |
| Protein-protein interaction assay | Cells expressing ARHGEF6 | Wild-type vs mutant ARHGEF6 | ARHGEF6-PARVA interaction | — |
| 3D cyst/lumen culture | Madin-Darby canine kidney (MDCK) cells | Expression of ARHGEF6-mutant proteins | Lumen formation and cell polarity | — |
| In vivo developmental phenotyping | Mouse (Arhgef6 deficiency) | Arhgef6 deficiency/KO | CAKUT-like renal/urinary tract phenotypes | — |
| In vivo developmental phenotyping | Frog (Xenopus, Arhgef6 deficiency) | Arhgef6 deficiency/knockdown | CAKUT-like renal phenotypes | — |
- – Six different hemizygous ARHGEF6 variants detected in eight individuals from six families with CAKUT
- ▲ Wild-type ARHGEF6 overexpression increased active CDC42/RAC1 levels, whereas mutant did not
- ▲ Wild-type ARHGEF6 induced lamellipodia formation and stimulated PARVA-dependent cell spreading; mutant did not
- ▼ ARHGEF6-mutant proteins lost interaction with PARVA
- ▼ 3D MDCK cultures expressing ARHGEF6-mutant proteins showed reduced lumen formation and polarity defects
- – Arhgef6 deficiency in mouse and frog recapitulated features of human CAKUT
- count 1265 families (International CAKUT cohort exome-sequenced)
- count six different hemizygous variants (ARHGEF6 variants detected)
- count eight individuals from six families (Individuals with CAKUT carrying ARHGEF6 variants)
- other about 40 disease genes (Known isolated CAKUT disease genes to date)
- other 20% (Proportion of CAKUT cases explained by known genes)
Statistical methods review
Model: sonnetA neutral, descriptive read of the statistical approach — what was done, and (for shared learning, not as criticism) what could also have been done.
The paper is a genetics/functional-genomics study combining exome sequencing of an international CAKUT cohort with cellular (kidney cell overexpression, 3D MDCK culture) and animal (mouse, frog) models. The provided text (title, author/affiliation block, and structured abstract with Background/Methods/Results/Conclusions) does not include a dedicated statistical methods section, so specific tests, sample-size justifications, or reporting details are not stated in the excerpt available.
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The study identifies candidate disease variants via exome sequencing across a large multi-family cohort (1265 families).↳ Could also: A formal statistical burden or case-control enrichment test (e.g., gene-based burden testing against a population reference such as gnomAD) could also be reported — This would give a quantitative estimate (e.g., odds ratio or p-value) of how unlikely the observed variant clustering in ARHGEF6 is under a null model, complementing the qualitative segregation/functional evidence described.
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Functional differences between wild-type and mutant ARHGEF6 were described qualitatively (e.g., 'increased active levels of CDC42/RAC1,' 'reduced lumen formation') based on cellular and 3D culture assays.↳ Could also: Quantifying these readouts (e.g., percentage of spheroids with a single lumen, active GTPase levels by densitometry) and comparing wild-type vs. mutant groups with a standard test such as an unpaired t-test, Mann-Whitney U, or a proportion test (e.g., Fisher's exact or chi-square) could also be used — Reporting a summary statistic with a measure of dispersion and a p-value or confidence interval would let readers gauge the magnitude and precision of the wild-type vs. mutant difference, alongside the descriptive phenotype.
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Multiple independent models (human cohort, kidney cell overexpression, 3D MDCK culture, mouse, and frog) are used to support the same conclusion about ARHGEF6 function.↳ Could also: A pre-specified analysis plan noting the number of biological/technical replicates per model and, where multiple phenotype endpoints are tested within a model, a multiple-comparison correction (e.g., Benjamini-Hochberg FDR or Bonferroni) could also be applied and reported — This would make explicit how many independent comparisons were run per model and control the chance of a false-positive finding when several endpoints (e.g., lamellipodia formation, cell spreading, lumen formation, polarity markers) are assessed together.
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Sample sizes/replicate counts for the in vitro and animal experiments are not stated in this excerpt.↳ Could also: Reporting the exact n for each experiment (e.g., number of independent transfections, embryos, or litters) and, where feasible, a power calculation or effect-size estimate could also be included — Explicit n and effect sizes help readers assess whether the study was adequately powered to detect the reported phenotypic differences between wild-type and mutant conditions.
What was reproduced
The exact results taken into scope, with each reported value next to the value our attempt produced.
Assessments & scoring basis
Each contributor’s verdict, the per-question basis, and the auditable, itemised worksheet behind it.
An automated assessment. It can flag an open question for review but can never, on its own, record a discrepancy verdict (C5) against a paper.
Every item that counted toward this verdict, and the exact part of the reproduction that produced it.
The in-silico annotation of Table 1 reproduces strongly on the paper's own 6-variant list (10 exact, 2 within-tol via gnomAD v2.1.1, CADD v1.6, REVEL, MutationTaster). Real deviations are confined to annotation-tool version/transcript drift — an honest SIFT flip for B3089 (Del→tolerated 0.098) and PolyPhen-2 0.36→0.092 (both still benign-range) — compounded by the paper not stating tool versions. The central discovery (1265 exomes→6 variants) and wet-lab work are not reproducible, but this is a data-availability/consent limit on the authors-vs-data axis, not a fabrication or computation defect. Overall a solid, explainable partial reproduction.
Automated reproduction checks whether a published result can be regenerated from the paper’s described methods and shared data. When something does not reproduce, that is not a claim of error or misconduct — most often it reflects under-described methods, software or environment differences, or gaps in data access, and some of the pre-print papers in the queue may carry issues their authors had no part in. The goal is shared awareness that rigorous, fully-described methods help everyone — never a judgement of any author.
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Reproduction footprint
claude-opus-4-8Measured resources invested to assess this paper — sanitised (machine class only, no job ids/paths). Compute = HPC accounting (SLURM); tokens = the AI agent's session.