An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome.
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
- ✓No relevant deviation in data/preprocessing
- ✓No authors-side cause for any deviation
- ✓Reported values are derivable from the shared data
- ✓Any deviation was negligible
- 🔴Could not use the authors’ exact input data
- 🟡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
Clinical case report (EJHG 2014): WES in 2 siblings found homozygous AP4B1 c.1160_1161delCA (p.(Thr387Argfs30), NM_006594.2), Sanger-confirmed, deposited to ClinVar (SCV000119895). PIPELINE-DERIVED SCOPE is thin and split: (a) the WES variant-discovery pipeline (C1) is NOT reproducible - raw exome reads were never deposited (no SRA/EGA/dbGaP; clinical patient data), an honest data-unavailable limit; (b) the downstream variant->protein annotation (C2/C3) IS reproducible and reproduces EXACTLY by two independent methods - VariantValidator (third-party tool on the paper's reported variant) and an independent hand-translation of RefSeq NM_006594.2 on «our HPC» both yield p.(Thr387Argfs30). Verdict: 1:1 EXACT for the computational annotation that has public inputs; the data-dependent discovery step is a documented drop. Overall = partial. NOT attempted: WES read alignment/variant calling (no data), Sanger confirmation (wet-lab), clinical phenotyping (manual). No fabrication concerns: the reported annotation is fully derivable from public RefSeq and corroborated independently in ClinVar.
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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 83assessed: 2026-06-19 ⛓ aeab64d5120a
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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: opusDo biallelic mutations in AP4B1 cause a phenotype consistent with AP-4 deficiency syndrome, and does identifying a novel AP4B1 mutation further support that loss of AP-4 complex assembly/function underlies the common clinical features across patients with mutations in any of the four AP-4 subunits?
- ★ A novel homozygous 2-bp deletion c.1160_1161delCA (p.(Thr387Argfs*30)) in AP4B1 was identified in two siblings with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia finding
- ★ The AP4B1 mutation segregated as expected: homozygous in both affected siblings and heterozygous in both unaffected parents finding
- ★ The highly similar clinical manifestations across patients with mutations in any of the four AP-4 subunits support that loss of AP-4 assembly or functionality underlies the common clinical features, supporting the existence of a clinically recognizable AP-4 deficiency syndrome mechanism
- Whole-exome sequencing is an effective approach to identify the causative mutation in this AP-4 deficiency phenotype method
- The AP4B1-associated phenotype, previously assigned to spastic paraplegia-47, falls within the broader AP-4 deficiency syndrome finding
| Assay | System | Perturbation | Readout | Platform |
|---|---|---|---|---|
| Whole-exome sequencing | Two affected siblings (human patients) from a non-consanguineous couple | none | Identification of pathogenic variants (homozygous AP4B1 deletion) | — |
| Sanger sequencing | Human family members (two affected siblings and both parents) | none | Confirmation and segregation/zygosity of the AP4B1 c.1160_1161delCA variant | — |
- – WES identified the novel homozygous AP4B1 2-bp deletion c.1160_1161delCA (p.(Thr387Argfs*30)) in both patients
- – Sanger sequencing confirmed the mutation as homozygous in the two siblings and heterozygous in both parents
- – Patients presented with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia, consistent with AP-4 deficiency syndrome
- count 2 siblings (patients) (affected individuals from a non-consanguineous couple studied)
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 is a short report describing a genetic case study of two siblings with intellectual disability and spastic tetraplegia. The paper used whole-exome sequencing to identify a homozygous frameshift mutation in AP4B1, followed by Sanger sequencing to confirm the variant in the affected siblings and its heterozygous presence in both parents. No statistical hypothesis testing, group comparisons, or quantitative statistical analysis appears in the available text.
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The paper identifies a candidate variant via whole-exome sequencing and confirms it with Sanger sequencing in the affected siblings and both parents.↳ Could also: Segregation analysis could also be formally summarized (e.g., reporting logarithm of odds/LOD-style segregation evidence or simple Mendelian segregation counts across the family), though this is more relevant for larger pedigrees. — In small families such as this one (two affected sibs, unaffected parents), qualitative segregation description is standard practice and formal statistical segregation analysis is typically not expected or informative.
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Pathogenicity of the AP4B1 variant is supported narratively through clinical/phenotypic similarity to previously reported AP-4 deficiency cases rather than through a formal statistical comparison.↳ Could also: A formal variant classification framework (e.g., ACMG/AMP criteria) or systematic phenotype-similarity scoring against a reference cohort could also be used to summarize the evidence for pathogenicity. — Such frameworks provide a structured, reproducible way to communicate the strength of genetic evidence, which can complement narrative case comparison, particularly when many case reports are later aggregated.
What was reproduced
The exact results taken into scope, with each reported value next to the value our attempt produced.
Scope — pmid-24781758
Paper: Abdollahpour H, Alawi M, Kortüm F, Beckstette M, Seemanova E, Komárek V, Rosenberger G, Kutsche K. An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome. Eur J Hum Genet. 2015 (online 2014-04). PMID 24781758 · PMCID PMC4297901 · DOI 10.1038/ejhg.2014.73.
What kind of paper
A clinical genetics case report. Two siblings of a non-consanguineous couple with
severe ID, absent speech, microcephaly, growth retardation and progressive spastic
tetraplegia. Whole-exome sequencing (WES) of the two affected siblings identified a
novel homozygous 2-bp deletion AP4B1 c.1160_1161delCA (p.(Thr387Argfs*30)),
transcript NM_006594.2. Sanger sequencing confirmed it in the siblings and showed
heterozygosity in both parents. The variant was submitted to ClinVar (SCV000119895).
In scope (pipeline-derived, computational)
| # | Reported result | Pipeline | Input availability | Verdict |
|---|---|---|---|---|
| C1 | WES of 2 siblings discovers the homozygous AP4B1 c.1160_1161delCA variant |
WES read alignment + variant calling + filtering (details only in Supplementary Methods) | Raw exome reads NOT deposited — no SRA/EGA/dbGaP; clinical patient data | NOT reproducible — data unavailable |
| C2 | Reported variant has protein consequence p.(Thr387Argfs*30) on NM_006594.2 |
HGVS variant→protein annotation (variant effect prediction) | Reported cDNA variant + public RefSeq NM_006594.2 — both available | REPRODUCED — exact (2 independent methods) |
Out of scope (wet-lab / manual / not computational)
- Sanger confirmation in siblings + parents (wet-lab).
- Clinical phenotyping, MRI, growth measurements (manual/clinical).
- No in-silico prediction tools (SIFT/PolyPhen/MutationTaster) were used by the authors.
- No authors' code repository exists; none claimed.
Reproduction strategy
The one computational result with public inputs is C2 (variant annotation). Reproduced two independent ways, both on the paper's own reported variant against the same transcript:
- Third-party tool — VariantValidator REST API on
NM_006594.2:c.1160_1161delCA. - Independent hand-translation on «our HPC» — fetched RefSeq NM_006594.2, located the CDS, deleted CDS positions 1160–1161, translated WT vs mutant with the standard genetic code.
C1 is an honest drop (sub-result): the raw WES data underlying the discovery was never deposited (clinical restriction), so the variant-calling pipeline cannot be re-run.
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.
Everything with public inputs reproduces 1:1 exactly: the reported c.1160_1161delCA / p.(Thr387Argfs*30) annotation is independently confirmed by both VariantValidator and a RefSeq hand-translation, and corroborated as Pathogenic/LP in ClinVar — no fabrication concern. The one gap is the WES variant-discovery step (C1), which is uncheckable because the raw clinical exome data was never deposited — a legitimate data-availability limit on the authors'/data side, not a methodological or computational defect of ours. Severity is negligible (exact matches everywhere comparable); overall is partial/yellow only because the core discovery rests on undeposited data, so its central claim is confirmed by proxy (annotation + ClinVar) rather than fully re-derived.
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.