A HS6ST2 gene variant associated with X-linked intellectual disability and severe myopia in two male twins

Leda Paganini, Loubna A. Hadi, Massimiliano Chetta, Davide Rovina, Laura Fontana, Patrizia Colapietro, Eleonora Bonaparte, Lidia Pezzani, Paola Marchisio, Silvia M. Tabano, Jole Costanza, Silvia M. Sirchia, Laura Riboni, Donatella Milani, Monica Miozzo

Research output: Contribution to journalArticlepeer-review


X-linked intellectual disability (XLID) refers to a clinically and genetically heterogeneous neurodevelopmental disorder, in which males are more heavily affected than females. Among the syndromic forms of XLID, identified by additional clinical signs as part of the disease spectrum, the association between XLID and severe myopia has been poorly characterized. We used whole exome sequencing (WES) to study two Italian male twins presenting impaired intellectual function and adaptive behavior, in association with severe myopia and mild facial dysmorphisms. WES analysis detected the novel, maternally inherited, mutation c.916G > C (G306R) in the X-linked heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) gene. HS6ST2 transfers sulfate from adenosine 3′-phosphate, 5′-phosphosulfate to the sixth position of the N-sulphoglucosamine residue in heparan sulfate (HS) proteoglycans. Low HS sulfation levels are associated with defective optic disc and stalk morphogenesis during mammalian visual system development. The c.916G>C variant affects the HS6ST2 substrate binding site, and its effect was considered “deleterious” by in-silico tools. An in-vitro enzymatic assay showed that the HS6ST2 mutant isoform had significantly reduced sulphotransferase activity. Taken together, the results suggest that mutant HS6ST2 is possibly involved in the development of myopia and cognitive impairment, characteristics of the probands reported here.

Original languageEnglish
Pages (from-to)368-374
JournalClinical Genetics
Issue number3
Publication statusPublished - 2019


  • HS6ST2
  • intellectual disability (ID)
  • syndromic myopia
  • whole exome sequencing (WES)

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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