Biallellic likely pathogenic/pathogenic variants in the ST3GAL5 gene were first reported in individuals with infantile-onset symptomatic epilepsy associated with developmental stagnation and blindness in 2004 (Simpson et al., PMID 15502825). Autosomal recessive “Salt and pepper developmental regression syndrome”, or GM3 synthase deficiency, was initially described in 1983 and is characterized by severe intellectual disability, microcephaly, midface hypoplasia, prominent lower face, scoliosis, choreoathetosis and spasticity. Phenotypic variability has been reported concerning mainly the occurrence of seizures and the presence of abnormal skin pigmentation (scattered hyper- and hypo- pigmented macules) at early stages. The most common underlying mechanism involves biparentally inherited loss-of-function ST3GAL5 variants leading to GM3 synthase deficiency. One recurrent nonsense variant was detected in 14 probands (PMIDs: 15502825, 22990144, 25131622, 30185102) and additional variants include one frameshift alteration (PMID: 34385424) and four missense variants in 8 probands (PMIDs: 24026681, 27232954, 30576498).
Functional studies indicated the absence of GM3 and derivatives in plasma samples (PMIDs: 15502825, 22990144, 24026681, 27232954) and fibroblasts (PMID: 24026681) from patients; as well as the complete loss of enzyme activity in transfected HEK-293T cells of expression plasmids carrying wild type and mutated ST3GAL5 cDNAs (PMID: 30576498).
In summary, ST3GAL5 is definitively associated with the autosomal recessive GM3 synthase deficiency as it has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. Approved by the ClinGen Epilepsy Gene Curation Expert Panel on April 5, 2022 (SOP version 8).
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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