Intellectual disability
Gene: HS6ST2

HS6ST2 (heparan sulfate 6-O-sulfotransferase 2)
EnsemblGeneIds (GRCh38): ENSG00000171004
EnsemblGeneIds (GRCh37): ENSG00000171004
OMIM: 300545, Gene2Phenotype
HS6ST2 is in 1 panel

4 reviews

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on phenotypes: OMIM phenotype updated 11th May 2026.
Created: 11 May 2026, 4:51 p.m. | Last Modified: 11 May 2026, 4:51 p.m.

Panel Version: 10.7

Comment on list classification: There are now 3 unrelated male individuals with hemizygous HS6ST2 variants and a neurodevelopmental syndrome (ID and/or GDD) - diagnosed with so called Paganini-Miozzo syndrome. Hence, this gene should be promoted to Green at the next update. MOI is set to X-LINKED: hemizygous mutation in males, biallelic mutations in females, as heterozygous mother of male sibs in PMID: 30471091 was not affected.
Created: 11 May 2026, 4:49 p.m. | Last Modified: 11 May 2026, 4:53 p.m.

Panel Version: 10.8

PMID: 30471091 Paganini et al., 2019
Two Italian male twins with intellectual disability and severe myopia and an X-linked hemizygous HS6ST2 variant c.916G>C, p.Gly306Arg (maternally inherited). Psychomotor delay diagnosed at 5 years. In-vitro enzymatic assay showed that the HS6ST2 mutant isoform had significantly reduced sulphotransferase activity.

PMID: 36993824 Sarmadian et al., 2023
Report of a 21mo boy from Iran, referred due to the absence of neck holding and hand tremors (manifestation of seizures). He had delayed developmental milestones such as neck holding, intellectual and walking impairment. Brain MRI showed cerebral atrophy and diffused white matter, and irregularities were seen in his EEG. He also had a ventricular septal defect. WES identified a hemizygous c.979C>T; p.Pro327Ser variant in HS6ST2 - classified as VUS, only 1 heterozygote reported in gnomAD v4.1.1.

PMID: 40686562 Zhang et al., 2025
Report of a 9 month old male Chinese proband with global developmental delay. WES detected a hemizygous c.764C>A (p.Pro255Glu) variant in HS6ST2. No abnormal vision. Brain CT scan revealed a wider left lateral ventricle compared to the contralateral ventricle.

Functional evidence: PMID: 38015989 Moon et al., 2024 - Knockout of Hs6st2 in mice decreases heparan sulfate 6-O-sulfation, impairs dendritic spines of hippocampal neurons, and affects memory, providing a link to human HS6ST2-related brain disorders.
Created: 11 May 2026, 4:47 p.m. | Last Modified: 11 May 2026, 4:55 p.m.

Panel Version: 10.8

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
?Paganini-Miozzo syndrome , OMIM:301025

Publications

Created: 11 May 2026, 4:47 p.m.
Last Modified: 11 May 2026, 4:55 p.m.
Panel version: 10.8

Louise Daugherty (Genomics England Curator)

Red List (low evidence)

No evidence for intellectual disability phenotype
Created: 18 Dec 2017, 3:36 p.m.

Created: 18 Dec 2017, 3:36 p.m.

Panel version: Imported from Intellectual disability update Dec 2017 panel version 0.39

Caroline Wright (Sanger)

Red List (low evidence)

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

Lu Raymond (university of cambridge )

Red List (low evidence)

Created: 23 Feb 2016, 11:18 a.m.

Panel version: 0.306

Details

Mode of Inheritance

X-LINKED: hemizygous mutation in males, biallelic mutations in females

Sources

Expert Review Amber

Phenotypes

?Paganini-Miozzo syndrome , OMIM:301025
Paganini-Miozzo syndrome, MONDO:0026724

Tags

Q2_26_promote_green

OMIM

300545

Clinvar variants

Variants in HS6ST2

Penetrance

Complete

Publications

Panels with this gene

Intellectual disability