Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum

Lina Basel-Vanagaite*, Tova Hershkovitz, Eli Heyman, Miquel Raspall-Chaure, Naseebullah Kakar, Pola Smirin-Yosef, Marta Vila-Pueyo, Liora Kornreich, Holger Thiele, Harald Bode, Irina Lagovsky, Dvir Dahary, Ami Haviv, Monika Weisz Hubshman, Metsada Pasmanik-Chor, Peter Nürnberg, Doron Gothelf, Christian Kubisch, Mordechai Shohat, Alfons MacayaGuntram Borck

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


Epileptic encephalopathies are genetically heterogeneous severe disorders in which epileptic activity contributes to neurological deterioration. We studied two unrelated children presenting with a distinctive early-onset epileptic encephalopathy characterized by refractory epilepsy and absent developmental milestones, as well as thick and short corpus callosum and persistent cavum septum pellucidum on brain MRI. Using whole-exome sequencing, we identified biallelic mutations in seizure threshold 2 (SZT2) in both affected children. The causative mutations include a homozygous nonsense mutation and a nonsense mutation together with an exonic splice-site mutation in a compound-heterozygous state. The latter mutation leads to exon skipping and premature termination of translation, as shown by RT-PCR in blood RNA of the affected boy. Thus, all three mutations are predicted to result in nonsense-mediated mRNA decay and/or premature protein truncation and thereby loss of SZT2 function. Although the molecular role of the peroxisomal protein SZT2 in neuronal excitability and brain development remains to be defined, Szt2 has been shown to influence seizure threshold and epileptogenesis in mice, consistent with our findings in humans. We conclude that mutations in SZT2 cause a severe type of autosomal-recessive infantile encephalopathy with intractable seizures and distinct neuroradiological anomalies.

Original languageEnglish
Pages (from-to)524-529
Number of pages6
JournalAmerican Journal of Human Genetics
Issue number3
StatePublished - 5 Sep 2013


FundersFunder number
Israeli Ministry of Health Chief Scientist Foundation3-4963
Ministerio de Ciencia y Competitividad
Deutsche ForschungsgemeinschaftNU50/8-1
Deutsche Forschungsgemeinschaft
Bundesministerium für Bildung und Forschung
Agència de Gestió d'Ajuts Universitaris i de RecercaSGR 2009/0078
Agència de Gestió d'Ajuts Universitaris i de Recerca
Israel Science Foundation558/09
Israel Science Foundation
Tel Aviv University
Instituto de Salud Carlos IIIPI12/01005
Instituto de Salud Carlos III


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