Split-Foot Malformation With Mesoaxial Polydactyly

A number sign (#) is used with this entry because of evidence that split-foot malformation with mesoaxial polydactyly (SFMMP) is caused by homozygous mutation in the ZAK gene (609479) on chromosome 2q31.

Clinical Features

Spielmann et al. (2016) studied a consanguineous Pakistani family in which 3 members had a split-foot malformation, which was bilateral in 2 and unilateral in 1. One affected individual also showed partial duplication of the second toe in combination with 1-2 and 4-5 cutaneous syndactyly, as well as duplication of the nail bed of the fourth finger bilaterally. In addition, all affected individuals had bilateral sensorineural hearing impairment. Spielmann et al. (2016) also studied a Tunisian boy with a very similar phenotype, including bilateral split-foot malformation, distal duplication of the second toe, and duplication of the nails of the fourth fingers. He had normal hearing and normal psychomotor development. Spielmann et al. (2016) designated the phenotype 'split-foot malformation with mesoaxial polydactyly (SFMMP).'

Mapping

In a multiplex consanguineous Pakistani family segregating split-foot malformation with mesoaxial polydactyly, Spielmann et al. (2016) performed SNP array genotyping and identified a 9.1-Mb linkage interval on chromosome 2q31 between SNPs rs836624 and rs6433931 with a maximum lod score of 3.5.

Molecular Genetics

In a multiplex consanguineous Pakistani family segregating a split-foot malformation with mesoaxial polydactyly mapping to chromosome 2q31, Spielmann et al. (2016) performed exome sequencing and identified homozygosity for a missense mutation in the ZAK gene (F368C; 609479.0001) that segregated with disease and was not found in 180 Pakistani controls or in public variant databases. The authors noted variable expressivity of the phenotype: 1 homozygous man did not exhibit the split-foot malformation, whereas his homozygous daughter was unilaterally affected. Screening of 106 unrelated patients with a broad range of split hand/foot malformations revealed a boy from Tunisia with a split-foot phenotype similar to that of the Pakistani family who was homozygous for an intragenic deletion in ZAK (609479.0002). His unaffected first-cousin parents were heterozygous for the deletion, which was not found in in-house or public CNV databases.