The SZT2 gene was first identified in 2009 in mice with reduced seizure threshold (Frankel et al., PMID:19624305). Later, in 2013, Basel-Vanagaite et al reported biallelic variants in patients with infantile encephalopathy with epilepsy and dysmorphic corpus callosum (PMID:23932106). More recently, SZT2 was revealed to play an important role in a novel protein complex called KICSTOR, a negative regulator of the mTOR pathway. Variants in SZT2 may lead to elevated mTorc1 signaling (PMIDs:28199306, 28199315).
Clinical features in individuals with biallelic variants in SZT2 include infantile- to early-onset epilepsy (onset within 1 day to 10 years), intellectual disability, developmental delay, macrocephaly with dysmorphic facial features, dysmorphic corpus callosum and dysregulated cortical migration. At least 13 unique variants reported in 7 probands were included in this curation (PMIDs: 23932106, 27248490, 28556953, 29696782, 30818181). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by experimental evidence including a mouse model (PMID:19624305).
In summary, SZT2 is definitively associated with autosomal recessive developmental and epileptic encephalopathy. This classification was approved by the Epilepsy Gene Curation Expert Panel on 02/02/2021 (SOP version 8).
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