Evidence for clinical and genetic heterogeneity of syndactyly type I: the phenotype of second and third toe syndactyly maps to chromosome 3p21.31.

There is good evidence from the medical literature that type I syndactyly, the most common form of the nonsyndromic syndactylies, is clinically heterogeneous. We therefore propose to group the condition into four subtypes, which are all autosomal dominantly inherited. Subtype 1, zygodactyly (cutaneous webbing of second and third toe without hand involvement) is the mildest and most common form. The phenotype varies from unilateral minor impression of webbing to bilateral complete webbing of second and third toe including a fusion of nails. Bony involvement is never observed. Subtype 2 is characterized by bilateral cutaneous and/or bony webbing of third and fourth finger, and second and third toe. The phenotype maps on chromosome 2q34-q36 and was designated as SD1 (ie syndactyly 1). The hallmark of subtype 3 is bilateral cutaneous or bony webbing of third and fourth finger, while subtype 4 shows bilateral cutaneous webbing of fourth and fifth toe. Both, subtype 3 and 4, are rare entities. Here, we present clinical and molecular data of a large Pakistani family with zygodactyly that was mapped to a new locus on chromosome 3p21.31 by genome-wide linkage analysis. The highest LOD score (Zmax=3.38) was obtained with microsatellite marker D3S2409. The disease interval is flanked by markers Chr3_4919 and Chr3_4940 encompassing about 0.20 Mb. Since the same phenotype appears not to be linked to this locus in a German family, we predict genetic heterogeneity in zygodactyly and propose to designate the 3p21.31 locus as ZD1 (i.e., zygodactyly 1).