ST3GAL5 – GM3 Synthase Deficiency

This summary integrates evidence linking ST3GAL5 (HGNC:10872) to GM3 synthase deficiency (MONDO:0018274), a severe neurodevelopmental disorder marked by infantile-onset epilepsy, profound intellectual disability, blindness, and movement abnormalities such as choreoathetosis (PMID:27232954, PMID:34906476). Multiple independent studies have reported affected individuals from diverse ethnic backgrounds, demonstrating a consistent autosomal recessive inheritance with affected siblings and extended segregation in familial cases (PMID:36833282).

In several case reports and multi-patient studies, both compound heterozygous and homozygous loss-of-function variants in ST3GAL5 have been identified. The variant spectrum includes frameshift, nonsense, and splice site variants. For example, one representative mutation, c.584G>C (p.Cys195Ser), has been reported in a pair of Korean siblings presenting with a Rett syndrome‐like phenotype, where the segregation analysis confirmed that unaffected parents were heterozygous carriers (PMID:27232954). Additional reports document other recurrent and founder variants supporting the genetic association.

Genetic evidence is further bolstered by detailed segregation data from multiple families. At least one affected relative has been documented in the index family, with additional families showing multiple affected individuals. Across the reviewed literature, more than 10 probands have been ascertained with similar variant classes and phenotypic presentations, underscoring the robustness of the association (PMID:24026681, PMID:34906476).

Functional studies have consistently demonstrated that pathogenic ST3GAL5 variants result in a complete or near‐complete loss of GM3 synthase activity. In vitro assays using patient-derived cells and model systems reveal markedly reduced synthesis of GM3 ganglioside, which is critical for neural tissue integrity. These experimental findings corroborate the genetic data and support a loss-of-function mechanism as the driver of the clinical phenotype (PMID:30576498).

No substantial conflicting evidence has emerged from the literature. While the phenotypic spectrum shows some variability – including additional features such as skin dyspigmentation and feeding difficulties in certain reports – the core neurological and developmental manifestations remain consistent, giving strong support for the clinical utility of this diagnostic marker.

In conclusion, the combined genetic, segregation, and functional evidence firmly establishes a strong association between ST3GAL5 variants and GM3 synthase deficiency. This correlation not only enhances diagnostic decision-making but also provides a foundation for commercial and translational applications.

Key Take‑home: ST3GAL5 variants lead to a loss-of-function in GM3 synthase activity, reliably causing a severe, early-onset neurodevelopmental disorder, with significant implications for clinical management and genetic counseling.

References

• American journal of medical genetics. Part A • 2016 • GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: Masquerading as Rett syndrome‑like phenotype PMID:27232954
• Human molecular genetics • 2014 • A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation PMID:24026681
• Genetics in medicine : official journal of the American College of Medical Genetics • 2022 • GM3 synthase deficiency in non‑Amish patients PMID:34906476
• Glycobiology • 2019 • Total loss of GM3 synthase activity by a normally processed enzyme in a novel variant and in all ST3GAL5 variants reported to cause a distinct congenital disorder of glycosylation PMID:30576498
• Genes • 2023 • Whole Exome Sequencing Reveals a Novel Homozygous Variant in the Ganglioside Biosynthetic Enzyme, ST3GAL5 Gene in a Saudi Family Causing Salt and Pepper Syndrome PMID:36833282

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