Deng Xinyue, Wu Shan, Deng Hao, Yuan Lamei
Xinyue Deng, Health Management Center, the Third Xiangya Hospital, Disease Genome Research Center, Center for Experimental Medicine, the Third Xiangya Hospital, Research Center of Medical Experimental Technology, the Third Xiangya Hospital, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China.
Shan Wu, MS, Health Management Center, the Third Xiangya Hospital, Disease Genome Research Center, Center for Experimental Medicine, the Third Xiangya Hospital, Research Center of Medical Experimental Technology, the Third Xiangya Hospital, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China.
Pak J Med Sci. 2025 Jan;41(1):263-268. doi: 10.12669/pjms.41.1.10153.
To identify the disease-causing variant in a family with tuberous sclerosis complex (TSC).
This study including a Han-Chinese pedigree recruited from the Third Xiangya Hospital, Central South University, Changsha, Hunan, China was conducted between February, 2019 and January, 2023. Detailed clinical examinations were performed on the proband and other family members of a Han-Chinese family with TSC. Whole exome sequencing of the proband and Sanger sequencing of all family members were performed, followed by variant pathogenicity prediction and conservation analysis. SWISS-MODEL and PyMOL software were used for protein modelling and creating the three-dimensional structure model illustration of the critical GTPase-activating protein (GAP) domain. The variant was classified following the American College of Medical Genetics and Genomics (ACMG) standards and guidelines.
The female proband exhibited typical features of TSC, including hypomelanotic macules, angiofibromas, shagreen patches, seizures, brain lesions, cognitive impairment, renal abnormalities, and cardiovascular abnormalities. A recurrent c.5126C>T variant in the TSC complex subunit 2 gene () was identified as the genetic cause of TSC in this family, classified as "pathogenic" according to ACMG standards and guidelines. The c.5126C>T variant leads to an amino acid change from proline to leucine at position 1709 (p.P1709L) in the functional GAP domain of tuberin protein, which may impair tumor growth inhibition of the hamartin-tuberin complex.
This study reported a Han-Chinese TSC patient with a recurrent variant c.5126C>T (p.P1709L). These findings broaden the phenotypic spectrum of TSC caused by this variant and may contribute to improving TSC genetic diagnoses as well as understanding of its mechanisms.
鉴定1例结节性硬化症（TSC）家系中的致病变异。
本研究于2019年2月至2023年1月进行，纳入了1个来自中国湖南长沙中南大学湘雅三医院的汉族家系。对1例患有TSC的汉族家系的先证者及其他家庭成员进行了详细的临床检查。对先证者进行了全外显子测序，并对所有家庭成员进行了Sanger测序，随后进行变异致病性预测和保守性分析。使用SWISS-MODEL和PyMOL软件进行蛋白质建模，并创建关键GTP酶激活蛋白（GAP）结构域的三维结构模型示意图。根据美国医学遗传学与基因组学学会（ACMG）的标准和指南对该变异进行分类。
女性先证者表现出TSC的典型特征，包括色素减退斑、血管纤维瘤、鲨革斑、癫痫发作、脑损伤、认知障碍、肾脏异常和心血管异常。在结节性硬化症复合物亚基2基因（ ）中鉴定出一个反复出现的c.5126C>T变异，被确定为该家系中TSC的遗传病因，根据ACMG标准和指南分类为“致病性”。c.5126C>T变异导致结节蛋白功能GAP结构域第1709位氨基酸由脯氨酸变为亮氨酸（p.P1709L），这可能损害错构瘤蛋白-结节蛋白复合物对肿瘤生长的抑制作用。
本研究报告了1例携带反复出现的c.5126C>T（p.P1709L）变异的汉族TSC患者。这些发现拓宽了由该变异引起的TSC的表型谱，可能有助于改善TSC的基因诊断及其机制的理解。
