摘要目的:探讨酪蛋白水解肽酶B同源物（caseinolytic peptidase B homolog， CLPB）基因变异所致3-甲基戊烯二酸尿症Ⅶ型的遗传学病因。 方法:回顾性分析1例在贵州医科大学附属医院诊断为3-甲基戊烯二酸尿症Ⅶ型患儿的分子生物学特征。提取患儿外周血白细胞DNA，应用高通量测序技术进行基因变异分析，并用Sanger测序进行家系验证。结果:患儿生后出现四肢强直、口周发绀，曾因“新生儿低钙血症、新生儿低血糖、新生儿黄疸（ABO溶血）”住院治疗。1岁1月龄因“发热4 d”后出现不能独坐、竖头不稳、进食呛咳，反复呼吸道感染，肌张力增高，尿代谢筛查示3-甲基戊烯二酸浓度为34.98 mmol/molCr。肌电图提示双侧腓总神经运动传导速度均渐慢，双侧腓浅神经感觉传导速度均轻度渐慢，且波幅均降低。脑电图在24 h内监测到18次癫痫临床发作。头颅MRI见脑发育欠佳，额叶及小脑为著；髓鞘化延迟。基因检测结果显示患儿 CLPB基因存在c.1016T>G（p.L339R）和c.130delG（p.E44Sfs*5）复合杂合变异；患儿母亲携带 CLPB基因c.1016T>G（p.L339R）杂合变异，患儿父亲携带 CLPB基因c.130delG（p.E44Sfs*5）杂合变异。患儿的变异分别来自父亲和母亲，均为未报道过的新变异。c.130delG（p.E44Sfs*5）杂合变异按照美国医学遗传学与基因组学学会指南评价为可能致病性。 结论:分别来自母亲和父亲的 CLPB基因c.1016T>G（p.L339R）和c.130delG（p.E44Sfs*5）复合杂合变异可能为该患儿的致病原因。

abstractsObjective:To investigate the genetic features of 3-methylglutaconic aciduria type Ⅶ caused by caseinolytic peptidase B homolog ( CLPB) gene variation. Methods:This study retrospectively analyzed the molecular biological features of a child diagnosed with 3-methylglutaconic aciduria type Ⅶ in the Affiliated Hospital of Guizhou Medical University. DNA samples were extracted from the peripheral white blood cells of the patient and analyzed using high-throughput sequencing to detect the genetic variants. Sanger sequencing was performed to validate the variants in the family.Results:The patient presented with limb rigidity and perioral cyanosis after birth and had been hospitalized for "neonatal hypocalcemia, neonatal hypoglycemia, and neonatal jaundice (ABO hemolysis)". After having a fever for four days at one year and one month of age, he could not sit up unaided or lift his head stably, and he coughed after eating. Moreover, recurrent respiratory infections and increased muscle tone also occurred. Screening for the metabolic markers in urine showed a 3-methylglutaric acid concentration of 34.98 mmol/molCr. Electromyography revealed the motor conduction velocity in the bilateral common peroneal nerves gradually slowed down and the sensory conduction velocity in the bilateral superficial peroneal nerves also slowed down slightly. Besides, there was a decrease in wave amplitude. Eighteen times of clinical seizures were monitored by electroencephalograph within 24 hours. Brain dysplasia, especially the frontal lobe and cerebellum, and delayed myelination were detected by cranial MRI. Genetic testing revealed the patient carried compound heterozygous variants of c.1016T>G(p.L339R) and c.130delG(p.E44Sfs*5) in the CLPB gene, which was inherited from his mother and father, respectively. Both variants were novel and unreported. According to the American College of Medical Genetics and Genomics guideline, the heterozygous variant c.130delG(p.E44Sfs*5) was potentially pathogenic. Conclusion:The compound heterozygous variants of c.1016T>G (p.L339R) and c.130delG (p.E44Sfs*5) in the CLPB gene inherited from his parents may be the cause of the disease in this patient.