EXT2 – Seizures-Scoliosis-Macrocephaly Syndrome

EXT2 encodes a glycosyltransferase essential for heparan sulfate chain elongation and extracellular matrix stability. Biallelic EXT2 variants have recently been linked to a novel autosomal recessive developmental disorder, seizures-scoliosis-macrocephaly syndrome (EXT2; Seizures-Scoliosis-Macrocephaly Syndrome).

In a consanguineous pedigree of four affected sibs, autozygosity mapping and exome sequencing identified homozygous EXT2 mutations c.283C>T (p.Arg95Cys) in all patients, each presenting with seizures, intellectual disability, hypotonia, macrocephaly, hypertelorism, and scoliosis ([PMID:26246518]). Segregation analysis confirmed autosomal recessive inheritance with three additional affected relatives carrying the variant ([PMID:26246518]).

A second unrelated family exhibited compound heterozygous missense variants, c.679G>A (p.Asp227Asn) and c.1823A>G (p.Tyr608Cys), expanding the phenotype to include multiple osteochondromas in two siblings, further supporting EXT2’s role in multisystem glycosylation disorders ([PMID:30288735]).

Functional assessment in patient fibroblasts demonstrated markedly reduced EXT2 protein levels and diminished glycosyltransferase activity. In vitro expression assays corroborated a dose-dependent decrease in heparan sulfate synthesis when either variant was expressed, with maximal loss when both mutations were combined ([PMID:26246518]).

Collectively, these genetic and experimental data fulfill ClinGen criteria for a strong gene–disease relationship. EXT2 should be included in diagnostic gene panels for neurodevelopmental syndromes with skeletal involvement. Key take-home: Biallelic EXT2 variants cause a defined autosomal recessive seizures-scoliosis-macrocephaly syndrome with potential for early molecular diagnosis and targeted counseling.

References

• Journal of medical genetics • 2015 • Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses. PMID:26246518
• Clinical genetics • 2019 • Novel exostosin-2 missense variants in a family with autosomal recessive exostosin-2-related syndrome: further evidences on the phenotype. PMID:30288735

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