SZT2 – Developmental and Epileptic Encephalopathy 18

Biallelic SZT2 variants cause developmental and epileptic encephalopathy 18 (DEE18), an autosomal recessive neurodevelopmental disorder marked by early‐onset refractory seizures and profound developmental delay. In a Chinese cohort, three unrelated patients harbored compound heterozygous variants in SZT2: c.2887A>G (p.Lys963Glu)/c.7970T>A, c.3508A>G (p.Ser1170Gly)/c.7936C>T, and c.2489T>G/c.8640_8641insC (p.Glu2881ArgfsTer14); structural modelling predicted disruption of SZT2–GATOR1 interaction and mTORC1 overactivation, and a literature review identified 27 additional affected individuals (PMID:35352205).

Trio‐based exome sequencing in six unrelated epilepsy cases revealed one de novo null variant and five pairs of biallelic variants with very low population frequency. Patients with biallelic null mutations exhibited severe DEE with spasms, tonic seizures, and cortical malformations, whereas those with biallelic missense variants had milder partial epilepsy with favorable outcomes, establishing a clear genotype–phenotype correlation (PMID:37213690).

Across all reports, at least 30 unrelated probands with SZT2 variants (including 16 predicted loss‐of‐function alleles: frameshift, in‐frame deletion, nonsense) have been documented, consistently in a recessive inheritance pattern, with no extended pedigree segregation beyond proband–parent trios.

Functional studies in patient‐derived cells demonstrated pathogenic mechanisms: impaired mitochondrial energy metabolism in lymphoblastoid lines with compound heterozygous variants (PMID:30564332), constitutive mTORC1 hyperactivation under both amino acid starvation and stimulation (elevated phospho-S6K/S6 and lysosomal mTOR localization) indicating loss of SZT2 inhibitory function (PMID:31430354), and a rapid mTORC1 assay identified a recurrent Ashkenazi Jewish founder in-frame deletion (p.Val2041del) as loss‐of‐function (PMID:35773235).

No studies to date have reported conflicting evidence for SZT2 in DEE18, and all variants studied functionally align with haploinsufficiency leading to mTORC1 hyperactivation. While additional VUS remain in larger cohorts, the current data saturate ClinGen genetic and experimental caps.

Collectively, biallelic SZT2 variants are a definitive cause of DEE18, with strong genetic and functional support; early genetic testing for SZT2 informs prognosis and may guide mTOR‐targeted therapeutic exploration.

References

• Neurological Sciences • 2022 • Genetic analysis of developmental and epileptic encephalopathy caused by novel biallelic SZT2 gene mutations in three Chinese Han infants: a case series and literature review PMID:35352205
• Frontiers in Molecular Neuroscience • 2023 • SZT2 variants associated with partial epilepsy or epileptic encephalopathy and the genotype-phenotype correlation PMID:37213690
• Clinical Case Reports • 2018 • Novel metabolic signatures of compound heterozygous Szt2 variants in a case of early-onset of epileptic encephalopathy PMID:30564332
• PLoS One • 2019 • Constitutive activation of mTORC1 signaling induced by biallelic loss-of-function mutations in SZT2 underlies a discernible neurodevelopmental disease PMID:31430354
• Epileptic Disorders • 2020 • Biallelic SZT2 variants in a child with developmental and epileptic encephalopathy PMID:32723703
• Brain • 2022 • mTORC1 functional assay reveals SZT2 loss-of-function variants and a founder in-frame deletion PMID:35773235

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