Curation SD5 HOXD13

Gene HOXD13

Disease SD5

Inheritance AD

Score

8.5 + 4 = 12.5 / 18

Genetic + experimental = total

Classification

Definitive

Refuted

Moderate

Definitive

Last Updated 08/18/2025

Pubs Reviewed 3

Publication Span 24.09 years

Publication Interval 24.09 years

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.

All criTRia Curations Locus Page

Genetic evidence

Total: 8.5

Per page

Category	Type	Citation	Score	Details
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

Per page

Category	Type	Citation	Score	Details
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.

Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.