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Autosomal recessive biallelic variants in ST3GAL3 underlie West syndrome, an age-dependent epileptic encephalopathy characterized by infantile spasms, hypsarrhythmia and developmental arrest. Four unrelated probands across two independent studies exhibit these hallmark features, with consistent genotype–phenotype correlations and supportive in vitro data (PMID:23252400)( PMID:30089820).
Inheritance of West syndrome due to ST3GAL3 is autosomal recessive. Three infants from a consanguineous pedigree were homozygous for c.958G>A (p.Ala320Thr) or c.958G>C (p.Ala320Pro), both disrupting an essential sialyl-motif and abolishing catalytic activity (PMID:23252400). A separate patient-derived iPSC study identified the recurrent c.958G>C (p.Ala320Pro) variant in an unrelated individual (PMID:30089820).
The variant spectrum in West syndrome is currently limited to recurrent missense changes at codon 320. No protein truncating or splice-site alleles have been reported in patients with classic West syndrome, suggesting that complete loss of ST3Gal-III enzymatic function is the critical disease mechanism.
Functional assays demonstrate a loss-of-function mechanism: p.Ala320Thr and p.Ala320Pro variants exhibit negligible sialyltransferase activity in HEK-293T cells (PMID:23252400). Patient-derived iPSC cortical neurons bearing p.Ala320Pro show altered lectin blotting, increased adhesion to poly-L-ornithine/laminin and reduced TBR1-positive neuronal populations, recapitulating key neurodevelopmental defects (PMID:30089820).
Together, genetic and experimental findings support haploinsufficiency of ST3GAL3 as the pathogenic mechanism, where impaired sialylation disrupts neuronal adhesion and maturation, precipitating epileptic spasms and cognitive impairment.
Based on four probands with concordant phenotypes and robust functional concordance, the ST3GAL3–West syndrome association is classified as ClinGen Moderate. ST3GAL3 sequencing should be included in diagnostic panels for early-onset epileptic encephalopathies to enable timely genetic diagnosis and inform patient management.
Gene–Disease AssociationModerate4 probands across two independent studies with consistent phenotypes and functional concordance Genetic EvidenceModerate4 affected individuals with biallelic ST3GAL3 missense variants including recurrent p.Ala320Pro PMID:23252400PMID:30089820 Functional EvidenceModerateLoss-of-function enzymatic assays and patient iPSC–derived neuronal models replicating disease features PMID:23252400PMID:30089820 |