Targeted genomic sequencing of TSC1 and TSC2 reveals causal variants in individuals for whom previous genetic testing for tuberous sclerosis complex was normal

West, Hannah D. ORCID: https://orcid.org/0000-0002-6104-6534, Nellist, Mark, Brouwer, Rutger W. W., van den Hout-van Vroonhoven, Mirjam C. G. N., de Almeida, Luiz Gustavo Dufner, Hendriks, Femke, Elfferich, Peter, Raja, Meera, Giles, Peter ORCID: https://orcid.org/0000-0003-3143-6854, Alfano, Rosa M., Peron, Angela, Sznajer, Yves, De Waele, Liesbeth, Jansen, Anna, Koopmans, Marije, Kievit, Anneke, Farach, Laura S., Northrup, Hope, Sampson, Julian R. ORCID: https://orcid.org/0000-0002-2902-2348, Thomas, Laura E. ORCID: https://orcid.org/0000-0002-8621-5285, van IJcken, Wilfred F. J. and Chen, Jian-Min 2023. Targeted genomic sequencing of TSC1 and TSC2 reveals causal variants in individuals for whom previous genetic testing for tuberous sclerosis complex was normal. Human Mutation: Variation, Informatics and Disease 2023 , 4899372. 10.1155/2023/4899372

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Abstract

Tuberous sclerosis complex (TSC) is caused by inactivating variants in TSC1 and TSC2. Somatic mosaicism, as well as the size and complexity of the TSC1 and TSC2 loci, makes variant identification challenging. Indeed, in some individuals with a clinical diagnosis of TSC, diagnostic testing fails to identify an inactivating variant. To improve TSC1 and TSC2 variant detection, we screened the TSC1 and TSC2 genomic regions using targeted HaloPlex custom capture and next-generation sequencing (NGS) in genomic DNA isolated from peripheral blood of individuals with definite, possible or suspected TSC in whom no disease-associated variant had been identified by previous diagnostic genetic testing. We obtained >95% target region coverage at a read depth of 20 and >50% coverage at a read depth of 300 and identified inactivating TSC1 or TSC2 variants in 83/155 individuals (54%); 65/113 (58%) with clinically definite TSC and 18/42 (43%) with possible or suspected TSC. These included 19 individuals with deep intronic variants and 54 likely cases of mosaicism (variant allele frequency 1-28%; median 7%). In 13 cases (8%), we identified a variant of uncertain significance (VUS). Targeted genomic NGS of TSC1 and TSC2 increases the yield of inactivating variants found in individuals with suspected TSC.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Medicine
Publisher:	Wiley
ISSN:	1098-1004
Date of First Compliant Deposit:	6 February 2024
Date of Acceptance:	3 June 2023
Last Modified:	13 Jun 2024 14:53
URI:	https://orca.cardiff.ac.uk/id/eprint/166143

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