Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.
The main results reproduced, with only marginal, non-material deviations.
Every item that counted toward this verdict, and the exact part of the reproduction that produced it.
- Nothing in this column.
- 🟡Could not use the authors’ exact input data
- 🟡Reported values were only indirectly comparable
- 🟡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
PMID 18834967 (Kim 2008, AJHG) is a wet-lab candidate-gene paper: Sanger sequencing of CHD7 in 197 IHH/KS patients found 7 mutations, validated by RT-PCR and in situ hybridisation. It deposited NO data, ships NO code, and has NO bioinformatic pipeline -> the bulk is out of scope and not reproducible by design. The only two in-silico claims were reproduced on «our HPC» with standard third-party tools: (R1) modern SIFT (Ensembl VEP r110) reproduces 4/5 of the paper's per-variant pathogenicity calls (S834F,H55R,P2880L deleterious; A2789T tolerated); only K2948E flips (paper deleterious -> modern tolerated_low_confidence), consistent with 18 yr of database growth and K2948 being the paper's least-conserved residue. (R2) MAFFT alignment of 119 CHD7 orthologs reproduces the two 'fully conserved' residues exactly (H55 99.1%, S834 99.1%); A2789/P2880/K2948 are conserved in the majority but the fine 'highly vs relative' ranking does not fully reproduce across a broad phylogeny. Overall: an honest PARTIAL reproduction of the paper's small computational footprint; the wet-lab core is not attemptable. NOT attempted: mutation discovery, RT-PCR, in situ, 3D modelling.
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Assessment versions
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v1 current initial assessment Score 70assessed: 2026-06-19 ⛓ 6fef82d59738
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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
- 2026-06-19
- 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: opusWe hypothesized that CHD7 would be involved in the pathogenesis of idiopathic hypogonadotropic hypogonadism and Kallmann syndrome (IHH/KS) without the CHARGE phenotype, and that IHH/KS represents a milder allelic variant of CHARGE syndrome.
- ★ Heterozygous CHD7 mutations cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome without the CHARGE phenotype. finding
- ★ Both normosmic IHH and KS are mild allelic variants of CHARGE syndrome caused by CHD7 mutations. mechanism
- ★ Sporadic CHD7 mutations occur in approximately 6% of IHH/KS patients. finding
- ★ CHD7 is the first identified chromatin-remodeling protein with a role in human puberty and the second gene to cause both normosmic IHH and KS in humans. finding
- ★ Three of the identified mutations affect chromodomains critical for CHD7 function in chromatin remodeling and transcriptional regulation. mechanism
- CHD7's role is corroborated by specific expression in IHH/KS-relevant tissues and appropriate developmental expression. finding
- SIFT and protein-structure analysis support that the missense mutations affecting conserved residues are deleterious. method
| Assay | System | Perturbation | Readout | Platform |
|---|---|---|---|---|
| Sanger mutation screening / DNA sequencing | 101 IHH/KS patients without CHARGE phenotype (human) | none | sequence variants in 37 protein-coding exons of CHD7 | — |
| Targeted exon sequencing | additional 96 IHH/KS patients (human) | none | sequence variants in exons 6–10 encoding conserved chromodomains | — |
| RT-PCR | patient samples (human) | none | splice variant / transcript analysis | — |
| In situ hybridization | IHH/KS-relevant tissues (developmental expression) | none | CHD7 spatial and developmental expression | — |
| In silico SIFT analysis | CHD7 protein sequence | none | predicted deleteriousness of missense variants | SIFT |
| Protein-structure analysis | CHD7 chromodomains | none | structural impact of mutations on chromodomain function | — |
- – Seven heterozygous mutations (two splice, five missense), absent in ≥180 controls, were identified in three sporadic KS and four sporadic normosmic IHH patients. 7 mutations
- – Three mutations affect chromodomains critical for proper CHD7 function; the other four affect conserved residues suggesting deleterious effect.
- – Sporadic CHD7 mutations occur in 6% of IHH/KS patients. 6%
- – CHD7 shows specific expression in IHH/KS-relevant tissues with appropriate developmental expression.
- count 101 IHH/KS patients (37 exons screened) (primary mutation screening cohort)
- count 96 IHH/KS patients (exons 6–10 screened) (additional chromodomain-focused cohort)
- count 7 heterozygous mutations (2 splice, 5 missense) (mutations identified across patients)
- count ≥180 controls (mutations absent in controls)
- count 7 patients (3 sporadic KS, 4 sporadic normosmic IHH) (patients carrying mutations)
- other 6% (frequency of sporadic CHD7 mutations in IHH/KS patients)
- count 37 protein-coding exons (exons of CHD7 sequenced)
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.
This report describes a genetic mutation-screening study rather than a hypothesis-testing statistical analysis: CHD7 exons were sequenced in cohorts of IHH/Kallmann syndrome patients (101 patients for all 37 exons, plus 96 additional patients for exons 6-10) and candidate variants were checked for absence in a control panel of at least 180 controls. Supportive evidence for pathogenicity came from in silico/functional approaches (RT-PCR, SIFT, protein-structure analysis, in situ hybridization) rather than inferential statistical tests. The text provided does not report p-values, effect sizes, or formal statistical comparisons.
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Pathogenicity of identified variants was supported by absence in ≥180 controls, described as a simple presence/absence comparison.↳ Could also: A formal case-control allele/genotype frequency comparison (e.g., Fisher's exact test) or population allele-frequency lookup in a reference database — This would let readers see a quantified estimate (e.g., an odds ratio or exact p-value) alongside the qualitative absence-in-controls observation, which can be useful when control panel sizes are modest.
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Variant deleteriousness was assessed using SIFT and protein-structure analysis as supportive in silico evidence.↳ Could also: Combining multiple in silico predictors (e.g., PolyPhen-2, CADD, or later-developed ensemble scores) alongside SIFT — Using several independent prediction algorithms can provide converging or complementary evidence about a variant's likely functional impact, which some readers find informative alongside a single predictor.
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The overall mutation frequency was reported as a single percentage (6% of IHH/KS patients) without an accompanying interval estimate.↳ Could also: Reporting a confidence interval around the proportion (e.g., a Wilson or Clopper-Pearson interval) — A confidence interval would convey the precision of the frequency estimate given the cohort size, which can be helpful for readers comparing this rate to other cohorts or genes.
What was reproduced
The exact results taken into scope, with each reported value next to the value our attempt produced.
Assessments & scoring basis
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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.
This is a 2008 wet-lab candidate-gene paper (CHD7 in IHH/Kallmann) that deposited no data and no code, so its central claim — discovery of 7 CHD7 mutations in 197 patients, with RT-PCR and in situ support — is out of scope and not computationally reproducible. The only reproducible footprint is two in-silico analyses, and these hold well: 4/5 SIFT pathogenicity calls are concordant and the two 'fully conserved' residues reproduce exactly (H55 99.1%, S834 99.1%). The deviations are not the authors' fault — K2948E flips deleterious->tolerated_low_conf(0.67) purely from ~18 yrs of SIFT database drift, and the C-terminal conservation tiers shift because of our self-chosen broad 119-ortholog alignment. Overall a solid, honest partial reproduction with explainable deviations and no fabrication concern.
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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.