Abstract：
OBJECTIVE: 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.
METHODS: 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.
RESULTS: The proband was a boy aged 1 year and 9 months with severe global developmental delay, transient drug-controlled 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: The proband was a boy aged 1 year and 9 months with severe global developmental delay, transient drug-controlled 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.
CONCLUSIONS: 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.
摘要：
目的：癫痫阈值2蛋白同源基因（SZT2，MIM：615463）相关疾病是极其罕见的常染色体隐性遗传疾病，具有从轻度智力障碍到严重发育性癫痫性脑病（DEE）的广泛临床表型。大多数SZT2相关疾病均伴有颅面畸形和call体畸形。本研究试图分析总结SZT2相关疾病的临床表型和遗传特点,为早期诊断提供依据,治疗,和预后。
方法：我们分析了一例SZT2致病变异的中国儿童的临床特征。我们还对患者进行了全外显子组测序(WES)。此外,我们对以前报道的SZT2基因致病突变患者进行了文献综述.
结果：先证者是一名1岁零9个月的男孩，患有严重的全球发育迟缓，短暂性药物控制的局灶性癫痫，丛集性癫痫,自闭症谱系障碍，颅面畸形,低张力,局灶性脑电图放电，call体畸形，和持续性透明隔腔。WES显示患者携带SZT2基因c.7584dupA和c.6302A>C复杂杂合变体；根据ACMG分类指南，前者可能是致病性的（LP），后者是不确定的意义（VUS）。根据我们的文献综述，迄今为止，已报道43例SZT2相关疾病；其中包括纯合子变异15例和复杂杂合子变异28例。共发现57种变异类型,包括47个遗传变异,2个从头变体，和8种未知的遗传模式。此外,发现2个高频变异(c.5949_5951delTGT和c.6553C>T)。40例患者主要临床表现为不同程度的整体发育迟缓(GDD)(38/40,95.00%),缉获量（36/40，90.00%），颅骨畸形（27/40，67.50%），面部畸形（22/40，55.00％），低张力（22/40，55.00％），脑电图异常发作（26/40，65.00％），背景活动缓慢（20/40，50.00%），胼胝体畸形(18/40,45.00%)。还有1例癫痫猝死（SUDEP）和3例因感染死亡。此外,三个具有相同变异的胎儿有脑积水和脑膨出。
结论：SZT2基因中c.7584dupA和c.6302A>C的复合杂合突变是该患者的遗传病因，扩展了SZT2相关疾病的突变谱。早期基因检测是明确诊断的最佳选择，治疗,和预后。
方法：我们分析了一例SZT2致病变异的中国儿童的临床特征。我们还对患者进行了全外显子组测序(WES)。此外,我们对以前报道的SZT2基因致病突变患者进行了文献综述.
结果：先证者是一名1岁零9个月的男孩，患有严重的全球发育迟缓，短暂性药物控制的局灶性癫痫，丛集性癫痫,自闭症谱系障碍，颅面畸形,低张力,局灶性脑电图放电，call体畸形，和持续性透明隔腔。WES显示患者携带SZT2基因c.7584dupA和c.6302A>C复杂杂合变体；根据ACMG分类指南，前者可能是致病性的（LP），后者是不确定的意义（VUS）。根据我们的文献综述，迄今为止，已报道43例SZT2相关疾病；其中包括纯合子变异15例和复杂杂合子变异28例。共发现57种变异类型,包括47个遗传变异,2个从头变体，和8种未知的遗传模式。此外,发现2个高频变异(c.5949_5951delTGT和c.6553C>T)。40例患者主要临床表现为不同程度的整体发育迟缓(GDD)(38/40,95.00%),缉获量（36/40，90.00%），颅骨畸形（27/40，67.50%），面部畸形（22/40，55.00％），低张力（22/40，55.00％），脑电图异常发作（26/40，65.00％），背景活动缓慢（20/40，50.00%），胼胝体畸形(18/40,45.00%)。还有1例癫痫猝死（SUDEP）和3例因感染死亡。此外,三个具有相同变异的胎儿有脑积水和脑膨出。
结论：SZT2基因中c.7584dupA和c.6302A>C的复合杂合突变是该患者的遗传病因，扩展了SZT2相关疾病的突变谱。早期基因检测是明确诊断的最佳选择，治疗,和预后。
