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Mutation landscape of TSC1/TSC2 in Chinese patients with tuberous sclerosis complex

Abstract

Genetic testing of TSC1 and TSC2 is important for the diagnosis of tuberous sclerosis complex (TSC), an autosomal dominant neurocutaneous disease. This study retrospectively reviewed 347 samples from patients with clinically suspected TSC being tested for mutations in TSC1 and TSC2 genes using next-generation sequencing and multiplex ligation-dependent probe amplification. Two hundred eighty-one patients (80.98%) were classified as definite/possible/uncertain diagnosis of TSC and the mutational spectrum of TSC1/TSC2 was described. Two hundred eighteen unique nonsynonymous SNVs/Indels (64 in TSC1, 154 in TSC2) and 13 copy number variants (CNVs) were identified in 241 samples (85.77%), including 82 novel variants. CNVs involving 12 large deletions and one duplication were detected exclusively in TSC2. Both TSC1 and TSC2 mutations were nearly uniformly distributed in their protein-coding regions. Furthermore, a string of non-TSC1/TSC2 deleterious variants in 12 genes was identified in the patients, especially overwhelmingly present in the patients with no mutation identified (NMI) in TSC1/TSC2. Our study provides a comprehensive TSC1/TSC2 mutation landscape and reveal some potential risk non-TSCs variants present in patients with NMI.

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Stylianos E. Antonarakis, Brian G. Skotko, … Roger H. Reeves

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Data availability data are available upon request.

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Acknowledgements

We are grateful to all the patients and families who contributed to this study. This study is supported by Science and Technology Program of Guangzhou, China (201604046001), Program for Entrepreneurial and Innovative Leading Talents of Guangzhou, China (CXLJTD-201603), Project of Academician Workstation at KingMed Diagnostics (2017B090904030) and National Natural Science Foundation of China (81870033).

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SY and WZ conceptualized the study; XY and MS collected the samples; YM, CY, MC and XY performed the data analysis; CY and HY performed biological experiments; YM and SY wrote the manuscript with input from all authors; all authors read and approved the final version of the manuscript.

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Correspondence to Weiwei Zhao or Shihui Yu.

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Meng, Y., Yu, C., Chen, M. et al. Mutation landscape of TSC1/TSC2 in Chinese patients with tuberous sclerosis complex. J Hum Genet 66, 227–236 (2021). https://doi.org/10.1038/s10038-020-00839-0

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