| Subtype/Mechanism | Locus/genes | Inheritance/penetrance notes | Key phenotype/extra features | Key 2023-2024 evidence source (citation id) | Publication (journal, date) and URL/DOI |
|---|---|---|---|---|---|
| **SHFM1 – 7q21 regulatory/coding defects** | **7q21.3**; **DLX5/DLX6** and long-range enhancers including **DYNC1I1 eExons 15/17** | Usually **autosomal dominant** with **incomplete penetrance** and **variable expressivity**; pathogenic mechanism often regulatory (enhancer deletion/separation) rather than coding loss alone (pqac-00000024, pqac-00000025, pqac-00000029) | Median cleft/split hand-foot; may include **hearing loss** (~35% in SHFM1 context), inner-ear anomalies, craniofacial anomalies, developmental delay in some rearrangements (pqac-00000024, pqac-00000039) | (pqac-00000024, pqac-00000023, pqac-00000029) | **Genes** (26 Jul 2023): Ambrosetti et al., *Split hand-foot and deafness in a patient with 7q21.13-q21.3 deletion not including the DLX5/6 genes*. https://doi.org/10.3390/genes14081526 ; **Frontiers in Molecular Biosciences** (Oct 2023): Sowińska-Seidler et al. https://doi.org/10.3389/fmolb.2023.1250714 |
| **SHFM3 – 10q24 structural-variant mechanism** | **10q24.31-q24.32**; **LBX1, BTRC, FBXW4, POLL** with altered regulation of the **LBX1/FGF8 locus** and AER enhancers in **FBXW4/Fgf8** domain | Usually **autosomal dominant**; marked **variable expressivity** and **reduced penetrance**; **mosaicism** documented in unaffected/less affected carriers; mechanism is chromatin/TAD rewiring by duplication or inversion (pqac-00000036, pqac-00000037, pqac-00000009, pqac-00000010) | Split hand/foot with central-ray deficiency; severity ranges from mild SHFM to severe limb deficiencies; some families show syndromic features (hearing/renal/craniofacial) depending on rearrangement extent (pqac-00000035, pqac-00000036) | (pqac-00000009, pqac-00000010, pqac-00000036) | **Nature Communications** (Mar 2023): Cova et al., *Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3*. https://doi.org/10.1038/s41467-023-37057-z ; **Frontiers in Genetics** (05 Jan 2024): Akimova et al. https://doi.org/10.3389/fgene.2023.1303807 ; **Orphanet Journal of Rare Diseases** (Oct 2024): Wang et al. https://doi.org/10.1186/s13023-024-03386-5 |
| **SHFM4 – TP63-related** | **3q28**; **TP63** | Typically **autosomal dominant**; **incomplete penetrance** documented; variable intrafamilial expression (pqac-00000003) | Isolated or syndromic ectrodactyly; classic central-ray absence/hypoplasia, sometimes with ectodermal findings depending on allele/syndrome context (pqac-00000003) | (pqac-00000003) | **Journal of Applied Genetics** (Oct 2014): Sowińska-Seidler et al., diagnostic/genetic overview including SHFM4. https://doi.org/10.1007/s13353-013-0178-5 |
| **SHFM6 – WNT10B-related** | **12q13.12**; **WNT10B** | **Autosomal recessive**; usually **homozygous** variants in consanguineous or multiplex families (pqac-00000045, pqac-00000047, pqac-00000048) | Non-syndromic SHFM with median clefts, missing central digits, complex syndactyly; some reports note dental anomalies/oligodontia and broader phenotypic variability (pqac-00000045, pqac-00000048) | (pqac-00000045, pqac-00000047) | **Molecular Syndromology** (20 Jun 2023): Bilal et al., *Sequence variants in the WNT10B underlying non-syndromic split-hand/foot malformation*. https://doi.org/10.1159/000531069 |
| **PRDM1 – newly implicated monogenic SHFM gene** | **PRDM1** (BLIMP1); limb regulatory targets include **fgfr1a, dlx5a, dlx6a, smo** in zebrafish fin/limb models | Appears **heterozygous** with **dominant-negative** mechanism; **incomplete penetrance/variable expressivity** reported in families (pqac-00000015, pqac-00000019, pqac-00000020) | SHFM with disruption of fin/limb induction, outgrowth, and AP patterning pathways; functional assays show failure to rescue fin defects and altered AER/AF-related gene regulation (pqac-00000015, pqac-00000016, pqac-00000020) | (pqac-00000015, pqac-00000016, pqac-00000020) | **Disease Models & Mechanisms** (Apr 2023): Truong et al., *PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation*. https://doi.org/10.1242/dmm.049977 |


*Table: This table summarizes the main SHFM loci and mechanisms most relevant for disease knowledge-base curation, emphasizing the best-supported 2023-2024 evidence for regulatory, structural-variant, and monogenic causes.*