Which HOX gene mutation is associated with human polysyndactyly (fusion of extra digits)?
HOXD13 is distal HoxA/D cluster member essential for autopod patterning, digit number, joint and interdigital separation. Polyalanine tract expansions, missense mutations altering homeodomain DNA binding disrupt downstream targets regulating BMP antagonism, interdigital apoptosis, and chondrogenic condensations. Resulting phenotype is synpolydactyly characterized by duplication and fusion of central digits, often with syndactyly. Mouse Hoxd13 knockouts show similar autopod defects, human pedigrees exhibit autosomal dominant inheritance with variable expressivity, confirming dosage-sensitive requirement of this transcription factor in distal limb morphogenesis and digit specification.
Ref: Gilbert, Developmental Biology, 12th ed., Chapter 19: HOXD13 mutation and human synpolydactyly.