| Topic | Validated human observation or numeric detail | Evidence type and important limitation | Citation IDs |
|---|---|---|---|
| Disease identifier | Acheiropodia; **OMIM/MIM 200500** | Explicitly reported in primary human literature; no unverified Orphanet or HPO identifiers included | (pqac-00000010, pqac-00000027) |
| Epidemiology | Historical incidence estimate in Brazil: **approximately 1 per 250,000 births** | Historical estimate cited in 2001; **not a modern prevalence or incidence measurement**; global rates are unknown | (pqac-00000010, pqac-00000027) |
| Core phenotype | Congenital, severe, bilateral transverse truncation of all four limbs, with absent hands, feet, and forearms; defects include distal humeral and tibial truncation and absence of the radius, ulna, fibula, and distal hand and foot bones | Human clinical observations from Brazilian families; published cohorts are extremely small | (pqac-00000003, pqac-00000010, pqac-00000026) |
| Phenotypic variation | Some affected individuals had an implanted residual digit, small finger-like appendages, or an ectopic **Bohomoletz bone** near the distal humerus | Human case-series evidence; frequencies were not quantified | (pqac-00000010, pqac-00000027) |
| Inheritance | Autosomal recessive; affected individuals were homozygous, whereas heterozygous parents were clinically unaffected; consanguinity was common in the original families | Human pedigree evidence; penetrance is supported within reported families but has not been estimated in a population cohort | (pqac-00000003, pqac-00000018, pqac-00000025) |
| Founder evidence | The same mutation and an approximately **1.3-cM shared haplotype** occurred in five unrelated Brazilian families, supporting inheritance from a common ancestor | Linkage and haplotype evidence from five families; mutation-age estimates were imprecise | (pqac-00000006, pqac-00000009) |
| Initial deletion definition, 2001 | PCR initially delimited a **4–6-kb** genomic deletion spanning **C7orf2/LMBR1 exon 4** | Primary human molecular study; boundaries were approximate because contemporary WGS was unavailable | (pqac-00000006, pqac-00000009) |
| Refined deletion definition, 2021 | WGS resolved a homozygous **12,041-bp** deletion at **GRCh38 chr7:156,816,030–156,828,070**, corresponding to **GRCh37/hg19 chr7:156,608,724–156,620,764**; a two-base **CA** insertion occurred at the breakpoint | Human WGS with PCR and Sanger validation in a proband and carrier parents; evidence concerns the recurrent Brazilian lesion rather than every possible acheiropodia allele | (pqac-00000001, pqac-00000005, pqac-00000018) |
| Original molecular interpretation | Exon 4 loss produced an exon 3–exon 5 junction, frameshift, and premature stop codon in exon 6; originally interpreted as a **C7orf2/LMBR1 null allele** | Human RNA evidence; this coding-loss interpretation was later supplemented by chromatin-architecture evidence | (pqac-00000006, pqac-00000009) |
| Revised regulatory interpretation | The 12-kb interval contains three CTCF sites, **LSC3–LSC5**, with RAD21 occupancy; deletion alters SHH-locus contacts and removes detectable ZRS–SHH-promoter interaction in proband cells | Patient-derived lymphoblastoid-cell ChIP-seq, 4C-seq, and DNA-FISH evidence; lymphoblasts are not embryonic limb-bud cells | (pqac-00000002, pqac-00000017, pqac-00000021) |
| ZRS status | The limb enhancer **ZRS remains physically intact** outside the deleted interval; no rare causal ZRS variant was identified, and the deleted sequence lacked consistent limb-enhancer activity | Human sequencing plus mouse transgenic reporter evidence; supports disrupted enhancer–promoter communication rather than deletion of ZRS | (pqac-00000004, pqac-00000018, pqac-00000019) |
| SHH expression | SHH expression was low in lymphoblastoid cells but significantly lower in proband cells than in wild-type cells | Human cell-line evidence; no fold-change was available, and embryonic limb expression was not measured directly | (pqac-00000021) |
| Mouse ortholog deletion | Homozygous deletion of the orthologous interval caused **no apparent limb phenotype** and no significant E11.5 autopod Shh-expression difference, **P = 0.7796** | Engineered mouse model; the negative result highlights species-specific CTCF architecture and limits direct phenotypic recapitulation | (pqac-00000002, pqac-00000008, pqac-00000017, pqac-00000024) |


*Table: Compact evidence table separating verified human findings from model-organism results and noting major limitations. It reconciles the original exon-loss interpretation with the later CTCF-mediated SHH regulatory mechanism.*