Rare missense variant p.Ala505Ser in the ZAK protein observed in a patient with split-hand/foot malformation from a non-consanguineous pedigree.

OBJECTIVE

Split-hand/foot malformation (SHFM) is a rare, often debilitating, congenital limb malformation. A single nucleotide polymorphism within the leucine zipper containing kinase AZK () gene was recently associated with SHFM in two consanguineous Pakistani pedigrees. We hypothesized that additional unrelated patients with the phenotype may carry a pathogenic mutation in .

METHODS

DNA samples were collected from 38 patients with SHFM and associated hearing loss for Sanger DNA sequencing and analysis.

RESULTS

Two missense mutations within were detected in 11 patients, but only one missense variant, p.Ala505Ser, occurred with a presumed rare allele frequency. modeling of the ZAK protein with the p.Ala505Ser substitution indicated a negative binding free energy change (mean ΔΔG = −0.9), representing destabilization of the ZAK tertiary structure. Additional laboratory analysis demonstrated a chromosome region 7q21.3-q22.1 deletion. This locus contains the SHFM-1 causative genes , , and (distal-less homeobox-5 and -6).

CONCLUSIONS

We report a novel and rare missense variant, ZAK p.Ala505Ser, in one patient with SHFM from a non-consanguineous pedigree. This variant mildly destabilizes the ZAK tertiary structure. Although this mutation involved a deletion at the locus (7q21.3-q22.1), ZAK signaling destabilization may have contributed to the phenotype, which included hearing loss.