HS6ST2 – Paganini-Miozzo Syndrome

HS6ST2 is implicated in X-linked recessive Paganini-Miozzo syndrome (Paganini-Miozzo syndrome). Four unrelated hemizygous males carrying novel missense variants—c.1099C>T (p.Pro367Ser) (PMID:36993824) and c.764C>A (p.Pro255Gln) (PMID:40686562)—present with global developmental delay (HP:0001263), cerebral atrophy (HP:0002059) and hand tremor (HP:0002378). Detailed familial segregation data are limited, but maternal carrier status is reported. Functional assays demonstrate that p.Pro255Gln reduces HS6ST2 protein expression in vitro (PMID:40686562), and Hs6st2 knockout mice exhibit decreased heparan sulfate 6-O-sulfation, dendritic spine deficits and memory impairment in line with human phenotype (PMID:38015989). These data support a loss-of-function mechanism for HS6ST2 in neurodevelopment. While additional segregation and variant spectrum studies are needed, HS6ST2 sequencing should be considered in male patients with unexplained intellectual disability and cerebral atrophy.

Key take-home: HS6ST2 mutation screening informs diagnosis of X-linked Paganini-Miozzo syndrome.

References

• Oxford Medical Case Reports • 2023 • A novel variant of Paganini-Miozzo syndrome: a case report. PMID:36993824
• Frontiers in Genetics • 2025 • A novel missense variant of HS6ST2 gene in Paganini-Miozzo syndrome with a rare neurodevelopmental and Endocrine phenotypes. PMID:40686562
• Glycobiology • 2024 • Knockout of the intellectual disability-linked gene Hs6st2 in mice decreases heparan sulfate 6-O-sulfation, impairs dendritic spines of hippocampal neurons, and affects memory. PMID:38015989

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