Genetic heterogeneity of synpolydactyly: a novel locus SPD3 maps to chromosome 14q11.2-q12.

Syndactyly type II or synpolydactyly (SPD) is the second most frequent syndactyly type and is inherited in an autosomal dominant fashion. The cardinal features of this malformation are the cutaneous or bony fusion of third and fourth fingers, and fourth and fifth toes associated with additional digital elements within the web. It shows incomplete penetrance and high inter- and intrafamilial phenotypic variability. Two loci are known for SPD (MIM 186000, MIM 608180) associated with mutations in HOXD13 and FBLN1, respectively. Here, we report further genetic heterogeneity for SDP. Employing a whole genomic screen, we demonstrate, in a large Pakistani kindred, that the classical phenotype of SPD maps on a new locus at chromosome 14q11.2-q12. The highest LOD score (Z(max) = 4.06) was obtained with microsatellite marker D14S264, and the multipoint LOD score reached a maximum of 5.01. Haplotype analysis revealed that the disease interval is flanked by microsatellite markers D14S283 and D14S1060, encompassing a physical distance of 10.72 Mb. We propose to allocate to this locus the symbol SPD3 (synpolydactyly 3), and to name the loci associated with HOXD13 or FBLN1 mutations SPD1 and SPD2, respectively.