To date, 20 different pathogenic variants have been described, all heterozygous missense variants or in-frame deletions. All pathogenic variants are localized in exon 1 and cluster into three mutational hotspots: amino acids 20-35, located in the R-SMAD binding domain, and amino acids 94-117 and 180, affecting the Dachshund-homology domain (DHD). This implicates that the initial molecular testing could be focused on mutation analysis of the first half of exon 1 of SKI. Interestingly, with a whole gene deletion (1p36.3 deletion syndrome) a patient does not present with SGS phenotype, suggesting that haplo-insufficiency is not the mechanism of action.
SKI