Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses

Abstract

In short, we have unravelled the genetic basis of a new recessive disorder, seizures-scoliosis-macrocephaly syndrome. Our results have implicated a well-characterised gene in a new developmental disorder and have further illustrated the spectrum of phenotypes that can arise due to errors in glycosylation.

Developmental delay, coarse facial features, and epilepsy in a patient with EXT2 gene variants

“…This syndrome includes phenotypes of developmental delay, intellectual disability, seizures, scoliosis, and micro/macrocephaly. Patients with this syndrome also have been reported to have coarse facial features, GI‐related issues, and poor speech . As illustrated in Table , our patient has overlapping features with this disorder, including macrocephaly, coarse facies, long philtrum, hypertelorism, strabismus, gastroesophageal reflux disease, constipation, sensitive skin, development/language delay, seizures, and delayed psychomotor development.…”

“…However, skeletal issues such as scoliosis and decreased bone density and muscular issues such as hypotonia, observed with this disorder, were not observed in our patient. There is clinical heterogeneity in this disorder, with two of four patients with biallelic EXT2 alterations noted to have a ventricular septal defect . The onset of this disorder is reported in infancy, with seizures starting between 2 and 5 years.…”

“…A number of inherited disorders are known to be caused by mutations in genes involved in the biosynthesis of heparan sulfate (HS), a linear polysaccharide that binds protein ligands, forming proteoglycans that are components of cell surfaces and extracellular matrices and are involved in many developmental processes . EXT2 (MIM: 608210) and NDST1 (MIM: 600853) are two such genes critical to the polymerization and processing of heparan sulfate.…”

“…EXT2 is implicated in the autosomal dominant disorder multiple Exostoses type 2 (MIM: 133701). Biallelic EXT2 mutations, however, have also been reported in four siblings born to consanguineous parents, manifesting scoliosis, seizures, and macrocephaly (MIM: 616682) without exostosis, following an autosomal recessive pattern of inheritance . Recently, two more families have been reported with multiple siblings in each displaying intellectual disability, facial dysmorphisms, and seizures with autosomal recessive EXT2 variants and this disorder has been renamed with the acronym AREXT2 (autosomal recessive EXT2‐related syndrome) .…”

Familial solitary chondrosarcoma resulting from germline EXT2 mutation

“…In the context of the mutated allele, this could subsequently modify the residual amount of functional EXT2 protein. It is noteworthy that germline biallelic mutations of the EXT2 gene do not result in MO but in a completely different phenotype corresponding to the Seizures‐Scoliosis‐Macrocephaly Syndrome, with no signs of MO (Farhan et al, ) suggesting that different levels of wild‐type EXT2 protein could determine different phenotypes.…”