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

Abstract

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.

Figure 1

Pedigrees and Pictures of Individuals with EOEE (A and B) Pedigrees of family 1 (A) and family 2 (B). Individuals affected or likely affected by EOEE are represented by filled black and gray symbols, respectively. The index individuals are depicted by arrows. The plus sign (+) denotes the reference sequence, and “mut” indicates the respective mutation. Red “mut” represents the c.73C>T (p.Arg25^∗) nonsense mutation, blue “mut” represents the c.1496G>T exonic splice-site mutation, and green “mut” represents the c.2092C>T (p.Gln698^∗) nonsense mutation. (C) Individual 1 at the age of 10 years (left) and individual 2 at the age of 9 years (right). Common facial dysmorphic features include a high forehead, downslanting palpebral fissures, ptosis, and arched and laterally extended eyebrows.

Figure 2

Brain MRI Findings Persistent cavum septum pellucidum (arrows) and thick and short corpus callosum (arrowheads) in the three affected children. (A and E) Individual II-5 at the age of 6 months. (B, C, F and G) Individual II-6 (individual 1) at the ages of 7 months (B and F) and 4 years and 8 months (C and G). (D and H) Individual 2 at the age of 2 years.

Figure 3

SZT2 Mutations (A) Homozygous nonsense mutation c.73C>T (p.Arg25^∗) detected in individual 1. (B) Compound-heterozygous mutation c.2092C>T (p.Gln698^∗) (left) and c.1496G>T (right) identified in individual 2. (C) RT-PCR on total RNA extracted from the blood of individual 2 and a control shows that the c.1496G>T exonic splice-site mutation leads to the skipping of exon 10.