SZT2 – Developmental and Epileptic Encephalopathy

SZT2 encodes a regulator of the mTORC1 signaling complex. Biallelic pathogenic variants in SZT2 have been implicated in Developmental and Epileptic Encephalopathy, an autosomal recessive disorder characterized by early-onset seizures, severe developmental impairment, and intellectual disability. The inheritance mode is autosomal recessive, confirmed by compound heterozygous variants in multiple unrelated families, with no evidence of dominant transmission.

Genetic evidence includes one detailed case report of a child with neonatal-onset seizures and suppression-burst EEG carrying c.2798C>T (p.Ser933Phe) and c.4549C>T (p.Arg1517Trp) (1 proband PMID:32723703), three Chinese infants with compound heterozygous variants (3 probands PMID:35352205), six unrelated patients in a genotype-phenotype correlation study (6 probands PMID:37213690), and five individuals reclassified with biallelic pathogenic variants via mTORC1 functional assay (5 probands PMID:35773235), totaling 15 probands across four cohorts. All identified variants include missense substitutions (e.g., p.Ser1170Gly, p.Lys963Glu), frameshift insertions causing p.Glu2881ArgfsTer14, and in-frame deletions such as p.Val2041del, consistent with loss-of-function.

Segregation analysis confirmed parental phase in all compound heterozygous cases, although no extended multi-generation pedigrees with multiple affected relatives have been reported. The variant spectrum is dominated by predicted loss-of-function alleles (nonsense, frameshift, in-frame deletions) and deleterious missense changes clustering in conserved domains. No recurrent or suspected founder variants have been reported in non-Ashkenazi populations; however, p.Val1984del was identified as an Ashkenazi Jewish founder in a separate cohort (PMID:35773235).

Functional studies demonstrate that SZT2 deficiency leads to constitutive hyperactivation of mTORC1 signaling: patient-derived lymphoblastoid cell lines show elevated phosphorylation of S6 kinase under amino acid starvation and constitutive lysosomal mTOR localization (PMID:31430354). Metabolic profiling in fibroblasts from a biallelic case revealed impaired mitochondrial energy metabolism, supporting a direct effect on neuronal bioenergetics (PMID:30564332). These data concord with the severe neurodevelopmental phenotype observed in patients.

No studies to date have disputed the association between SZT2 and autosomal recessive developmental and epileptic encephalopathy. Variant reclassification efforts have further strengthened genotype-phenotype correlations by resolving variants of uncertain significance into pathogenic categories.

Together, the genetic and functional evidence supports a Strong ClinGen classification for SZT2 in developmental and epileptic encephalopathy. Additional cohort studies and longitudinal follow-up will refine phenotype severity correlations and potential therapeutic targets within the mTOR pathway. Key take-home: SZT2 biallelic loss-of-function variants cause a severe autosomal recessive encephalopathy via mTORC1 dysregulation, justifying genetic testing in early-onset epileptic encephalopathy.

References

• Epileptic disorders : international epilepsy journal with videotape | 2020 | Biallelic SZT2 variants in a child with developmental and epileptic encephalopathy. PMID:32723703
• Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 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
• Brain : a journal of neurology | 2022 | mTORC1 functional assay reveals SZT2 loss-of-function variants and a founder in-frame deletion. PMID:35773235
• 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

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