Snyder-Robinson syndrome is caused by hemizygous loss of function mutations in the SMS gene, on chromosome Xp22.11. Point mutations have been reported thus far.
Molecular genetics
Pathogenic variants in SMS include missense, splice-site variants and one truncating mutation. All the pathogenic variants lead to loss of function of the protein. The pathogenic SMS variant can arise de novo in the affected individual, or can be inherited from an unaffected carrier mother.
Genotype-phenotype correlations are not available due to the paucity of reported individuals.
The SMS gene encodes for the protein spermine synthase (SMS), involved in polyamine metabolism. Spermine synthase functions as a dimer composed of two identical monomers, and converts spermidine into spermine. Pathogenic variants in SMS lead to very low levels of SMS activity. This leads to increased spermidine/spermine ratio and low spermine.
The diagnosis of Snyder-Robinson syndrome is obtained when a pathogenic variant of SMS is detected. Since an increasing number of variants in this gene are being detected by means of whole exome sequencing and gene panels, the only way to confirm pathogenicity of a variant is to perform enzyme activity assay.