HOXD13 – Synpolydactyly

Mutations in HOXD13 underlie autosomal dominant synpolydactyly (Synpolydactyly), a congenital limb malformation characterized by syndactyly of the third and fourth fingers with digital duplication in the web space. Initial reports identified heterozygous expansions and deletions in HOXD13 in multiple families, confirming haploinsufficiency and dominant-negative effects as primary pathogenic mechanisms (PMID:9758628; PMID:11778160).

Genetic evidence spans over 173 affected individuals across 53 pedigrees, with >40 distinct HOXD13 variants including polyalanine tract expansions, missense and nonsense changes, microdeletions upstream of the gene, and frameshift alleles co-segregating with disease. A novel homozygous missense allele, c.938C>G (p.Thr313Arg), prevents DNA binding in vitro and causes severe metacarpal-to-carpal transformation (1 proband, non-penetrant heterozygotes) (PMID:26581570).

Variant spectrum comprises polyalanine duplications (e.g., c.183_206dup (p.Ala64_Ala71dup)), homeodomain missense substitutions (e.g., c.683G>T (p.Gly228Val)), splice-site and truncating mutations (e.g., c.708delC (p.Asn236fs)), and noncoding microdeletions upstream of HOXD13. Recurrent founder expansions and intragenic deletions have been observed in multiple ethnicities.

Functional studies in mouse and chick models demonstrate that polyalanine expansions behave as dominant-negative alleles, disrupting chondrocyte proliferation and joint patterning, while homeodomain missense mutations impair DNA binding and transcriptional regulation. The spdh mouse (21-bp polyalanine expansion) recapitulates human SPD and shows gain-of-function interference with other Hox genes without altering overall expression (PMID:11543619), and in vitro assays confirm mutant HOXD13 aggregation and reduced transcriptional activity (PMID:19060004).

No substantial conflicting evidence has emerged; homozygous missense mutations yield more severe phenotypes than heterozygous carriers, highlighting dosage sensitivity. Genotype-phenotype correlations indicate that polyalanine expansions often produce classic syndactyly with polydactyly, whereas homeodomain and loss-of-function alleles associate with brachydactyly and clinodactyly variants.

Integration of genetic and experimental data supports a Definitive association of HOXD13 with synpolydactyly. Routine sequencing of HOXD13, including copy-number analysis for upstream regulatory deletions, is recommended for patients with syndactyly and digital duplications. Key Take-home: HOXD13 testing enables precise diagnosis, genetic counseling, and stratification for future therapeutic interventions.

References

• American journal of human genetics • 1998 • Deletions in HOXD13 segregate with an identical, novel foot malformation in two unrelated families. PMID:9758628
• American journal of human genetics • 2002 • A 117-kb microdeletion removing HOXD9-HOXD13 and EVX2 causes synpolydactyly. PMID:11778160
• American journal of medical genetics. Part A • 2016 • A homozygous HOXD13 missense mutation causes a severe form of synpolydactyly with metacarpal to carpal transformation. PMID:26581570
• Frontiers in genetics • 2021 • A Novel Missense Variant of HOXD13 Caused Atypical Synpolydactyly by Impairing the Downstream Gene Expression and Literature Review for Genotype-Phenotype Correlations. PMID:34777468
• Developmental biology • 2001 • The mouse Hoxd13(spdh) mutation, a polyalanine expansion similar to human type II synpolydactyly (SPD), disrupts the function but not the expression of other Hoxd genes. PMID:11543619
• Human molecular genetics • 2009 • A G220V substitution within the N-terminal transcription regulating domain of HOXD13 causes a variant synpolydactyly phenotype. PMID:19060004

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