The SMS gene has been associated with syndromic X-linked intellectual disability Snyder type in (at least) 10 probands in 8 publications. At least 9 unique variants (missense, out-of-frame-splice) have been reported in humans, and variants in this gene segregated with disease in at least 12 additional family members. SMS was first associated with this disease in humans in 2003 (Cason et al.). The mechanism for disease is thought to be that variants that destabilize the dimer cause loss of the SMS protein, leading a dearth of sperimine which is an essential developmental polyamine. This has been demonstrated by animal models, expression studies, functional alteration studies, and analysis of the crystal structure of SMS (Wu 2008, Zhange 2013, Wang 2011, Peng 2016, Zhang 2011, Li 2018, Pegg 2009, Pegg 2011). In summary, SMS is definitively associated with syndromic X-linked intellectual disability Snyder type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
SMS was first reported in relation to syndromic X-linked intellectual disability Snyder type in 2003 (Cason et al., PMID: 14508504). Nine unique variants (missense, out-of-frame-splice) that have been reported in 10 probands in 9 publications (PMIDs: 14508504, 18550699, 19206178, 22612257, 23696453, 25888122, 26174906, 26350204, 26761001) are included in this curation. Variants in this gene segregated with disease in at least 12 additional family members. The mechanism of pathogenicity is loss of function. Variants that destabilize the dimer cause loss of the SMS protein, leading to a dearth of sperimine, which is an essential developmental polyamine. This has been demonstrated by animal models, functional alteration studies, and analysis of the crystal structure of SMS.
In summary, there is definitive evidence supporting the relationship between SMS and syndromic X-linked intellectual disability Snyder type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on May 16, 2018 (SOP Version 5).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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