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

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

doi:10.1111/cge.13485

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.

Highlights

Intellectual disability (ID) gene density is high on the X chromosome, with more than 10% of all ID-related proteincoding genes mapping to the X, establishing the condition referred to as X-linked ID (XLID) that predominantly occurs in males[6]; overall, 30% more males are affected than females.[7]
The pedigree of the family included in this study was consistent with the presence of a de novo variant or with recessive autosomal or X-linked inheritance, and filtering processes revealed the missense substitution c.916G>C in the heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) gene as the unique candidate variant with high confidence
This variant was never been previously reported and encodes HS6ST2, which transfers sulphate from PAPS to the N-sulphoglucosamine (GlcNS) residue in heparan sulfate (HS) proteoglycans

Summary

| INTRODUCTION

Gupta et al reviewed the candidate genes related with inherited myopia and reported only two forms of non-syndromic condition, one involving ZNF644 and the other related to SCO2 gene.[8] High myopia and severe ID, presenting as isolated manifestations without other relevant dysmorphic or malformative features, have never been previously associated with a known clinical condition. They have been identified in many syndromes, such as Donnai-Barrow or Cohen syndromes, as part of a broad range of clinical signs affecting many parts of the body.

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION