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A HS6ST2 gene variant associated with X‐linked intellectual disability and severe myopia in two male twins
Author(s) -
Paganini Leda,
Hadi Loubna A.,
Chetta Massimiliano,
Rovina Davide,
Fontana Laura,
Colapietro Patrizia,
Bonaparte Eleonora,
Pezzani Lidia,
Marchisio Paola,
Tabano Silvia M.,
Costanza Jole,
Sirchia Silvia M.,
Riboni Laura,
Milani Donatella,
Miozzo Monica
Publication year - 2019
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13485
Subject(s) - heparan sulfate , genetics , mutant , exome sequencing , allele , gene , exome , intellectual disability , biology , mutation , medicine , cell
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.