Abstract
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 language | English |
|---|---|
| Pages (from-to) | 368-374 |
| Journal | Clinical Genetics |
| Volume | 95 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2019 |
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Keywords
- HS6ST2
- intellectual disability (ID)
- syndromic myopia
- whole exome sequencing (WES)
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
A HS6ST2 gene variant associated with X-linked intellectual disability and severe myopia in two male twins. / 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.
In: Clinical Genetics, Vol. 95, No. 3, 2019, p. 368-374.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A HS6ST2 gene variant associated with X-linked intellectual disability and severe myopia in two male twins
AU - Paganini, Leda
AU - Hadi, Loubna A.
AU - Chetta, Massimiliano
AU - Rovina, Davide
AU - Fontana, Laura
AU - Colapietro, Patrizia
AU - Bonaparte, Eleonora
AU - Pezzani, Lidia
AU - Marchisio, Paola
AU - Tabano, Silvia M.
AU - Costanza, Jole
AU - Sirchia, Silvia M.
AU - Riboni, Laura
AU - Milani, Donatella
AU - Miozzo, Monica
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - HS6ST2
KW - intellectual disability (ID)
KW - syndromic myopia
KW - whole exome sequencing (WES)
UR - http://www.scopus.com/inward/record.url?scp=85059071141&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85059071141&partnerID=8YFLogxK
U2 - 10.1111/cge.13485
DO - 10.1111/cge.13485
M3 - Article
AN - SCOPUS:85059071141
VL - 95
SP - 368
EP - 374
JO - Clinical Genetics
JF - Clinical Genetics
SN - 0009-9163
IS - 3
ER -