Synpolydactyly 2

A number sign (#) is used with this entry because synpolydactyly-2 (SPD2) is caused by disruption of the fibulin-1 gene (FBLN1; 135820).

For a general phenotypic description and a discussion of genetic heterogeneity of synpolydactyly, see SPD1 (186000).

Clinical Features

De Smet et al. (1996) reported a Belgian family in which a father and daughter had a syndrome with metatarsal fusion, metacarpal fusion, and synpolydactyly between the third and fourth fingers. Debeer et al. (1998) reported a second affected daughter. Inheritance was autosomal dominant. At first, De Smet et al. (1996) considered the manifestations typical of the Cenani-Lenz type of syndactyly (212780), which is autosomal recessive. The authors suggested that earlier reported cases of Cenani-Lenz syndrome in sibs of normal parents may have been due to gonadal mosaicism or that Cenani syndactyly is genetically heterogeneous with autosomal recessive and autosomal dominant forms. However, based on pattern of inheritance, involvement of the feet, and the synpolydactyly, Debeer et al. (1998, 1998) concluded that the malformations in the family reported by De Smet et al. (1996) could not be classified as Cenani-Lenz syndactyly or any previously described type of syndactyly. Moreover, they failed to find expansion of a polyalanine stretch within the first exon of the HOXD13 gene (142989), which resides on 2q31 and had been shown to be a cause of synpolydactyly (186000). Debeer et al. (1998, 1998) referred to the syndrome in their family as a complex type of '3/3-prime/4 synpolydactyly associated with metacarpal and metatarsal synostoses.'

Cytogenetics

Debeer et al. (1998) found that the malformation in the father and daughters in the family described by De Smet et al. (1996) cosegregated with an apparently balanced translocation, t(12;22)(p11.2;q13.3).

Mapping

As a first step toward the positional cloning of a candidate disease gene on chromosome 12 and/or 22 responsible for the type of complex synpolydactyly observed in the family described by De Smet et al. (1996), Debeer et al. (1998) constructed a somatic cell hybrid retaining only the der(22) of the t(12;22). By STS content mapping and fluorescence in situ hybridization experiments, they positioned the chromosomal breakpoints between markers D12S1596 and D12S1034 on chromosome 12p and markers N73F4 and D22S158 on chromosome 22. Debeer et al. (2000) presented a physical map around the 12p11.2 breakpoint, established a 1.5-Mb contig, and found a rearranged BamHI fragment in the patients with the translocation.

Molecular Genetics

By molecular analysis of the reciprocal translocation region t(12;22)(p11.2;q13.3) found in the family described by De Smet et al. (1996), Debeer et al. (2002) found involvement of an alternatively spliced exon of the fibulin-1 gene on chromosome 22q13 and the C12ORF2 (HoJ-1) gene (608231) on chromosome 12p. The breakpoint was located in the intron between the last 2 exons of the FBLN1-D splice variant isoform (exons 19-20) and interrupted the 5-prime untranslated region of C12ORF2. Fibroblasts derived from the patients displayed decreased levels of FBLN1-D incorporated into the extracellular matrix and secreted into the cultured medium, whereas expression of the FBLN1-C variant was normal. Debeer et al. (2002) concluded that the translocation results in haploinsufficiency of the FBLN1-D variant, which could lead to the observed limb malformations. The authors noted that the entire FBLN1 gene is deleted in the chromosome 22q13.3 deletion syndrome (606232).