Compound heterozygous SZT2 mutations in two siblings with early-onset epilepsy, intellectual disability and macrocephaly

Abstract

Mutations in SZT2 have been previously reported in several cases of early onset epilepsy and intellectual disability. In this study we investigate potential causal mutations in two male siblings affected by early onset epilepsy, intellectual disability and macrocephaly. Methods: We use family-based whole-exome sequencing to identify candidate variants. Results: We report the identification of two potential causal SZT2 mutations in compound heterozygous state. We observe considerable differences in the clinical phenotype severity of the two affected individuals. The cerebral MRI revealed no abnormalities in the older affected brother, while in the youngest one it revealed a right frontal polymicrogiria. Moreover, while good seizure control was achieved in the older affected individual the younger brother is affected by pharmacoresistant epilepsy, progressive spastic paraplegia, cortical myoclonus and a more severe intellectual disability. We also analyzed the relative location of the reported pathogenic mutations in the SZT2 protein. Conclusion: Variable phenotypic expressivity is observed for this condition, while the location and type of mutations in SZT2 also has a potential impact on epilepsy severity. These findings extend our knowledge of epileptogenic conditions related to SZT2 and mTOR signaling.

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.…”

“…SZT2 mutation‐related cases have also been reported, presenting mainly with heterogeneous phenotypes ranging from mild‐moderate intellectual disabilities (ID) without seizures (Falcone et al, ), to early‐onset epileptic encephalopathy with severe ID (Pizzino et al, ). Despite the reports of more than 10 cases (Domingues et al, ; Pizzino et al, ) of epileptic encephalopathies harboring SZT2 mutations, the clinical features due to SZT2 mutations remain to be elucidated. Here, we report three cases carrying two heterozygous compound mutations and summarize the clinical features, with the aim of expanding our knowledge of the phenotypes and genotypes of SZT2‐related DEEs.…”

Determining the pathogenicity of variants of uncertain significance and identification of a founder variant in the epilepsy-associated gene,SZT2

“…However, none of the individuals in these groups had corpus callosum abnormalities, including those with P/LP variants, suggesting that this is not a cardinal feature of SZT2 -associated epilepsy. Moreover, a genotype-phenotype correlation has been suggested; individuals bearing truncating mutations may be more likely to have intractable seizures than individuals with missense variants 12 . In this cohort, we observed more variability, with individual 2 (bi-allelic truncations) having seizure onset at two months with intractable seizures, while the other individual with intractable seizures (with seizure onset at two days of life) carried a multi-exon in-frame deletion and a VUS (Table S4, S5).…”

A novel possible familial cause of epilepsy of infancy with migrating focal seizures related to SZT2 gene variant

“…11 Characteristically, hypotonia and facial dysmorphism, including a high forehead and to a lesser extent ptosis and down-slanting palpebral fissures, were present in the majority of reported patients including ours. 4,11,12 Although no genetic testing was done on the first child, as the WES was not available in our institution at the time, she was almost certainly affected by the same condition in view of her indistinguishable dysmorphic features, and essentially identical clinical course, EEG findings, and seizure semiology.…”