Snyder-Robinson Syndrome, Spermine Synthase Deficiency via the SMS Gene

Snyder-Robinson syndrome is characterized by mild to moderate X-linked intellectual disability, seizures, speech and gait abnormalities, marfanoid habitus, hypotonia and movement disorders, skeletal changes caused by osteoporosis, facial dysmorphism with a prominent lower lip, nasal voice, high, narrow or cleft palate, and long, thin fingers and toes (Cason et al. 2003; Becerra-Solano et al. 2009; Albert et al. 2015).

Affected males present reduced spermine synthase activity, correspondingly low levels of intracellular spermine in lymphocytes and fibroblasts, and elevated spermidine/spermine ratios (Cason et al. 2003). Carrier females are clinically normal (Becerra-Solano et al. 2009). Hypothetically, female carriers could develop symptoms due to skewed inactivation of X chromosome.

Snyder-Robinson syndrome is inherited in an X-linked recessive manner and is caused by pathogenic variants in the SMS gene encoding the polyamine biosynthetic enzyme spermine synthase. Spermine synthase is ubiquitously expressed and is responsible for the conversion of spermidine to spermine. Spermine, a polyamine, is known to be essential for normal cell growth, maintenance and survival (Cason et al. 2003; Kesler et al. 2009; Pegg and Michael 2010; Albert et al. 2015). The possible functions of spermine include resistance to reactive oxygen species and to other stress, ion channel regulation and bone development (Pegg 2014).

Pathogenic variants in SMS gene lead to greatly reduced spermine synthase activity and protein content. It was hypothesized that the tissue specificity of Snyder-Robinson syndrome arises from differential sensitivity to spermidine toxicity or spermine deficiency (Albert et al. 2015).

To date, pathogenic variants in SMS include only missense and one splice pathogenic variant. No large deletions or duplications have been reported in SMS (Becerra-Solano et al. 2009; Zhang et al 2013; Albert et al. 2015; Human Gene Mutation Database).

Clinical sensitivity is difficult to predict as only a few patients have been reported as case studies. Analytical sensitivity should be high as all reported pathogenic variants are detectable by DNA sequence analysis (Human Gene Mutation Database).

No large deletions or duplications have been reported in SMS (HGMD).

This test provides full coverage of all coding exons of the SMS gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.