SD5_HOXD13
- Gene
- HOXD13
- Disease
- SD5
- Inheritance
- AD
- Classification
- Definitive
- Total Score
- 12.5
- Publications Reviewed
- 3
- Publication Span
- 24.09 years
- Last Updated
- 08/18/2025
- Curator(s)
- Macayla Weiner, Laurel Hiatt
Description
Autosomal dominant synpolydactyly type 5 is associated with in-frame polyalanine expansions in exon 1 of HOXD13, a coding tandem-repeat tract outside the DNA-binding homeodomain. Published families show HOXD13 polyalanine expansions segregating with synpolydactyly, with expansion size correlating with penetrance and limb phenotype severity. Functional studies in a Hoxd13 +7A synpolydactyly mouse model and transcription-factor condensate assays support a repeat-expansion mechanism that alters HOXD13 condensate composition and downstream transcriptional programs during limb development.
Genetic evidence
Total: 8.5
| Singular Evidence | Probands | PMID:9207113 | 6 | Sixteen newly ascertained SPD pedigrees and 4 previously published pedigrees were clinically/genetically reviewed; HOXD13 exon 1 polyalanine expansions of +7, +8, +9, +10, or +14 alanines were identified, with 99 affected individuals examined. |
| Collective Evidence | Allele | PMID:9207113 | 1 | Across 20 SPD pedigrees, larger HOXD13 polyalanine expansions correlated with higher penetrance and greater limb involvement; nonpenetrance was observed only with the smallest (+7 alanine) expansions, and severity increased significantly for hands (P=0.012) and feet (P<0.00005). |
| Collective Evidence | Segregation | PMID:8614804 | 1.5 | In three SPD pedigrees, HOXD13 polyalanine expansion alleles cosegregated with synpolydactyly; affected individuals carried larger PCR products, one homozygous individual had a more severe phenotype, and one clinically unaffected relative was a nonpenetrant heterozygous carrier. |
Experimental evidence
Total: 4
| Models | Non-human model organism | PMID:32386547 | 4 | Homozygous spdh mouse embryos carrying the Hoxd13 +7A repeat-expansion allele showed synpolydactyly-relevant limb bud defects, altered HOXD13-containing condensates, reduced co-activator overlap, and cell-type-specific transcriptional changes in disease-relevant limb cells. |
Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.