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Genetic analysis of 18 families with tuberous sclerosis complex

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Abstract

Tuberous sclerosis complex (TSC) is mainly caused by variants in TSC1 and TSC2, which encodes hamartin protein and tuberin protein, respectively. Here, we report clinical and molecular characteristics of 18 families with TSC. High-throughput DNA sequencing was employed to detect variants in all the exons and flanking region of TSC1 and TSC2. TA clone and real-time PCR were performed to verify the pathogenicity of candidate variants. A total of 17 mutations were identified, including 13 mutations in TSC2 and 4 mutations in TSC1. Fifty-six percent (10/18) of the families carried de novo mutations, and 8 of these mutations were not reported previously. Most mutations detected were loss-of-function mutations (15/17). One splice-site mutation (TSC2 c.599 + 5G > A) caused abnormal splicing and was confirmed by in vitro analysis. Facial angiofibromas (94%) and epilepsy (89%) were the most prevalent clinical features in our patients. Treatment with anti-seizure medication (ASM) or in combination with rapamycin results in clinical remission in most patients with TSC-associated seizures (14/15). For genotype–phenotype correlation, patients in our cohort with TSC2 mutations had an earlier onset age and patients with TSC1 showed better response to ASM. Our study has expanded the spectrum of TSC1 and TSC2 causing TSC.

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Acknowledgements

We thank all patients and their family members for their collaboration.

Funding

The study was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (Grant number: 2021-I2M-1–034, 2021-I2M-1–018, 2016-I2M-1–002), National Natural Science Foundation of China (NSFC; grant numbers 81971293, 81788101), National Key Research and Development Program of China (Grant number: 2016YFC0905100), and Research Fund from CAAE (UCB-2018029).

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Authors and Affiliations

  1. Mckusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China

    Kaili Yin & Xue Zhang

  2. Department of Neurology, Peking Union Medical College Hospital (PUMCH), CAMS & PUMC, Beijing, China

    Nan Lin, Qiang Lu, Liri Jin, Yan Huang, Xiangqin Zhou & Qing Liu

  3. Department of Respiratory, Peking Union Medical College Hospital (PUMCH), CAMS & PUMC, Beijing, China

    Kaifeng Xu

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  1. Kaili Yin
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Correspondence to Qing Liu.

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Yin, K., Lin, N., Lu, Q. et al. Genetic analysis of 18 families with tuberous sclerosis complex. Neurogenetics 23, 223–230 (2022). https://doi.org/10.1007/s10048-022-00694-5

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