Biallelic mutations in SZT2 cause a discernible clinical entity with epilepsy, developmental delay, macrocephaly and a dysmorphic corpus callosum

Novel metabolic signatures of compound heterozygous Szt2 variants in a case of early‐onset of epileptic encephalopathy

“…Furthermore, we provide novel evidence of metabolic and mitochondrial dysfunctions by these compound heterozygous Szt2 variants, shedding light on the potential pathophysiologic mechanism and genotype‐phenotype correlations. Since 2013, up to 15 Szt2 variants have been identified in patients with early‐onset epileptic encephalopathy . Although these patients exhibit heterogeneous clinical phenotypes, they all show developmental delay to various degrees with or without epilepsy, most likely correlated to the residual functions of the SZT2 protein.…”

“…Although these patients exhibit heterogeneous clinical phenotypes, they all show developmental delay to various degrees with or without epilepsy, most likely correlated to the residual functions of the SZT2 protein. Biallelic truncating mutations cause the most extreme phenotypic manifestations, such as severe developmental delay, profound intellectual disability, the absence of speech, facial dysmorphism, focal epileptic discharges, pectus carinatum, and a thick and short corpus callosum . In contrast, missense Szt2 variants are associated with mild phenotype including moderate intellectual disability without seizures, most likely as a result of residual SZT2 functions …”

“…Compound heterozygous frameshift and nonsense Szt2 variants were detected in a young child presenting a different phenotype characterized by developmental delay, cognitive deficiencies, and most importantly abnormal perisylvian gyral configuration suggestive of abnormal cortical development due to abnormal neuronal migration . Since then, additional novel pathogenic Szt2 variants have been identified by WES in related and unrelated patients exhibiting a range of phenotypes …”

“…7 Since then, additional novel pathogenic Szt2 variants have been identified by WES in related and unrelated patients exhibiting a range of phenotypes. 8,9 In this study, we report the case of a young patient harboring compound heterozygous Szt2 variants, the maternally inherited substitution variant of uncertain significance mapping in exon 36 and the paternally inherited in-frame three-base-pair-deletion variant, likely pathogenic, mapping in exon 42. The proband exhibits severe global developmental delay, hypotonia, cognitive deficiencies, and transient seizures following a hypoxic-ischemic event closely after birth.…”

Novel SZT2 mutations in three patients with developmental and epileptic encephalopathies

“…To our knowledge, since the first case reported by Basel et al (Basel‐Vanagaite et al, ) in 2013, only 21 cases (Basel‐Vanagaite et al, ; Domingues et al, ; Falcone et al, ; Imaizumi, Kumakura, Yamamoto‐Shimojima, Ondo, & Yamamoto, ; Kariminejad et al, ; Nakamura et al, ; Naseer et al, ; Pizzino et al, ; Tsuchida et al, ; Venkatesan et al, ) (including the three cases presented here) carrying SZT2 mutations have been reported to date. The phenotypes were largely heterogeneous and formed a continuum of characteristics from early‐onset epileptic encephalopathy to mild ID without epilepsy, which may be associated with the alteration in residual protein function because truncating mutations cause complete loss of SZT2 function.…”