• Xinyue Deng, Shan Wu, Hao Deng, and Lamei Yuan.
• 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.
• Pak J Med Sci. 2025 Jan 1; 41 (1): 263268263-268.

ObjectiveTo identify the disease-causing variant in a family with tuberous sclerosis complex (TSC).MethodsThis 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.ResultsThe 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 (TSC2) 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.ConclusionThis study reported a Han-Chinese TSC patient with a recurrent variant TSC2 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.Copyright: © Pakistan Journal of Medical Sciences.

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