TSC2/PKD1邻接基因综合征的临床特征及遗传学分析：病例系列研究

刘欣婷; 敦硕; 陈娜; 陈健; 万林; 梁妍; 朱刚; 张璟; 刘国寅; 邹丽萍; 杨光

doi:10.12435/j.issn.2095-5227.2024.050

TSC2/PKD1邻接基因综合征的临床特征及遗传学分析：病例系列研究

Clinical characteristics and genetic analysis of TSC2/PKD1 contiguous gene syndrome: A case series

摘要

摘要:
背景 TSC2/PKD1邻接基因综合征(TSC2/PKD1 contiguous deletion syndrome，PKDTS)是TSC2 与 PKD1 基因缺失导致的疾病，国内鲜有报道。
目的总结5例TSC2/PKD1邻接基因综合征患儿的临床表型和遗传学特征。
方法回顾性分析2015—2023年于解放军总医院儿科就诊的4例PKDTS患儿以及于山东第一医科大学附属省立医院就诊的1例PKDTS患儿病例资料，采集患儿及其父母的外周血样，分别利用不同的分子生物学方法进行基因检测。
结果 5例PKDTS患者均以癫痫起病，有相似的临床特征，包括皮肤色素脱失斑、颅内结节、多囊肾、肾功能异常、高血压等，伴有不同程度的发育迟缓，兼具结节性硬化(TSC)和常染色体显性多囊肾疾病(autosomal dominant polycystic kidney disease，ADPKD)的表型。雷帕霉素可以辅助控制TSC相关癫痫发作；严重肾囊肿患者需要穿刺抽液 + 药物凝固治疗来缓解症状。基因检测结果显示5例患儿分别存在TSC2/PKD1基因不同大小和区域的缺失：病例1，chr16:2131595-2264778区域存在133.18 kb的缺失；病例2，TSC2基因31 ~ 42号外显子和PKD1基因30 ~ 46号外显子缺失，长度17.64 kb；病例3，chr16:g.2114201-2185990区域存在缺失，长度为71.789 kb；病例4，chr16:2125441-2176668区域缺失拷贝数51.22 kb；病例5，16p13.3(16:2099825-2151077)区域缺失，覆盖51.25 kb。
结论本研究发现TSC2/PKD1缺失程度与临床症状的严重程度之间没有明确关联。利用全基因组测序可以早期精准诊断PKDTS并进行干预，雷帕霉素联合抗癫痫发作药物可较好控制TSC相关癫痫。

Abstract:
Background TSC2/PKD1 contiguous deletion syndrome (PKDTS) is caused by the deletion of TSC2 gene and PKD1 gene, which has been rarely reported in China.
Objective To summarize the clinical phenotype and genetic characteristics of 5 cases with PKDTS.
Methods Clinical data about five children with PKDTS from 2015 to 2023 in Chinese PLA General Hospital and Provincial Hospital Affiliated to Shandong First Medical University were collected and analyzed retrospectively. Peripheral blood of the patients and their parents were collected for genetic testing. Different molecular biology methods, such as whole exome sequencing, gene panel, whole genome sequencing, long segment PCR, Sanger sequencing and multiplex ligation-dependent probe amplification, were used for gene testing.
Results Five patients with PKDTS all started with epilepsy, had similar clinical characteristics, including skin leukoplakia, intracranial nodules, polycystic kidney, renal dysfunction, hypertension, etc., accompanied by varying degrees of developmental delay, which fused the phenotypes of tuberous sclerosis (TSC) and autosomal dominant polycystic kidney disease (ADPKD). Rapamycin could control TSC related epilepsy well, and patients with severe polycystic kidney disease could use tovastatin and fluid extraction + drug coagulation surgery to alleviate symptoms. The results of genetic testing showed that 5 children had TSC2/PKD1 gene deletions in different length and regions: Case 1, chr16: 133.18 kb missing in the 2131595-2264778 region; Case 2, TSC2 gene exon 31-42 and PKD1 gene exon 30-46 were missing, with a length of 17.64 kb; Case 3, chr16: g. 2114201-2185990 area had a missing length of 71.789 kb; Case 4, chr16: 2125441-2176668 region had a deletion of copy number 51.22 kb; Case 5, 16p13.3 (16:2099825-2151077) region were missing, covering 51.25 kb.
Conclusion A summary of 5 PKDTS cases shows no significant correlation between the location and length of gene deletions and the severity of clinical symptoms. The use of whole genome sequencing can accurately diagnose PKDTS in the early stage and intervene. Rapamycin combined with anti-epileptic drugs can effectively control TSC related epilepsy.

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