Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract

Abstract

Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation. Typical cases have 3/4 finger and 4/5 toe syndactyly, with a duplicated digit in the syndactylous web, but incomplete penetrance and variable expressivity are common. The condition has recently been shown to be caused by expansions of an imperfect trinucleotide repeat sequence encoding a 15-residue polyalanine tract in HOXD13. We have studied 16 new and 4 previously published SPD families, with between 7 and 14 extra residues in the tract, to analyze the molecular basis for the observed variation in phenotype. Although there is no evidence of change in expansion size within families, even over six generations, there is a highly significant increase in the penetrance and severity of phenotype with increasing expansion size, affecting both hands (P = 0.012) and feet (P < 0. 00005). Affected individuals from a family with a 14-alanine expansion, the largest so far reported, all have a strikingly similar and unusually severe limb phenotype, involving the first digits and distal carpals. Affected males from this family also have hypospadias, not previously described in SPD, but consistent with HOXD13 expression in the developing genital tubercle. The remarkable correlation between phenotype and expansion size suggests that expansion of the tract leads to a specific gain of function in the mutant HOXD13 protein, and has interesting implications for the role of polyalanine tracts in the control of transcription.

Figure 1

Pedigrees of 16 new SPD families. Solid symbols represent individuals with SPD. Dotted symbols represent phenotypically normal mutation carriers.

Figure 2

Polyalanine tract sequence in 20 SPD pedigrees. Across the top is a normal 15-residue sequence. Below the sequence are expansions (boxed) in SPD pedigrees. Probable sites of insertion of duplicated regions are indicated by vertical arrows. Note that many of these expansions could be interpreted as insertions of the same-sized duplications at a different site. Alanine 12 is encoded by GCG in pedigrees B, G–J, M, O, and P.

Figure 3

Bar charts showing correlation between expansion size and number of hands (A) and feet (B) affected in SPD patients.

Figure 4

Bar chart showing correlation between expansion size and level of branching in SPD hands with digit duplication.

Figure 5

The limb phenotype in pedigree Q. Photograph (A) and x-ray (B) of right hand of II.1 at age 5 years and 18 months, respectively, showing severe SPD (duplicated third finger with soft tissue syndactyly as far as distal phalanx, bifid third metacarpal, fifth finger camptodactyly, and middle phalanx hypoplasia of all fingers), as well as broad, radially deviated thumb with short first metacarpal. (C) X-ray of right hand of II.2 at age 8 years, showing similar severe SPD, with soft tissue syndactyly as far as proximal phalanx, as well as an enlarged capitate bone. (D) X-ray of left foot of II.4 at age 6 years, showing severe SPD (additional toe between fourth and fifth toes; additional metatarsal between fourth and fifth metatarsals; middle phalanx hypoplasia of toes 2–5; and absent middle phalanx of toe 6, with bracket epiphysis of proximal phalanx), as well as broad hallux, with pseudoarthrosis at base of first and second metatarsals.