Clinical phenotype and genetic characteristics of SZT2 related diseases: A case report and literature review

Purpose: Seizure threshold 2 protein homolog gene (SZT2, MIM: 615463) related diseases are extremely rare autosomal recessive disorders with a wide spectrum of clinical phenotypes ranging from mild intellectual impairment to severe developmental epileptic encephalopathy (DEE). Most SZT2 related diseases are accompanied by craniofacial malformation and corpus callosum malformation. This study attempts to analyze and summarize the clinical phenotype and genetic characteristics of SZT2 related diseases, providing a basis for early diagnosis, treatment, and prognosis.Method: We analyzed the clinical characteristics of a Chinese child with pathogenic variants of SZT2. We also performed whole-exome sequencing (WES) on the patient. In addition, we conducted a literature review of previously reported patients with pathogenic mutations in the SZT2 gene.Result: The proband was a boy aged 1 year and 9 months with severe global developmental delay, transient drugcontrolled focal epilepsy, cluster epilepsy, autism spectrum disorder, craniofacial deformity, hypotonia, focal EEG discharge, corpus callosum malformation, and persistent cavum septum pellucidum. WES revealed that the patient carried the SZT2 gene c.7584dupA and c.6302A>C complex heterozygous variants; the former being Likely Pathogenic (LP) and the latter Uncertain Significance (VUS) according to ACMG classification guidelines. According to our literature review, 43 cases of SZT2 related diseases have been reported so far; these include 15 cases with homozygous variations and 28 cases with complex heterozygous variations. A total of 57 types of variation were found, including 47 genetic variants, 2 de novo variants, and 8 unknown genetic modes. In addition, 2 high-frequency variants were found (c.5949_5951delTGT and c.6553C>T). The main clinical manifestations of the 40 patients were global developmental delay (GDD) of varying degrees (38/40, 95.00 %), seizures (36/40, 90.00 %), cranial deformity (27/40, 67.50 %), facial deformity (22/40, 55.00 %), hypotonia (22/40, 55.00 %), abnormal interseizure EEG discharge (26/40, 65.00 %), slow background activity (20/40, 50.00 %), corpus callosum deformity (18/40, 45.00 %). There was also one case of sudden unexpected death in epilepsy (SUDEP) and 3 cases of death from infection. In addition, three fetuses with the same variant had hydrocephalus and encephalocele.Conclusion: The compound heterozygous mutation of c.7584dupA and c.6302A>C in the SZT2 gene is the genetic etiology of this patient, expanding the mutation spectrum of SZT2 related diseases. Early genetic testing is the best choice for clear diagnosis, treatment, and prognosis.