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Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal

Hannah D. West, Mark Nellist Orcid Logo, Rutger W. W. Brouwer, Mirjam C. G. N. van den Hout-van Vroonhoven, Luiz Gustavo Dufner de Almeida, Femke Hendriks, Peter Elfferich, Meera Raja, Peter Giles, Rosa M. Alfano, Angela Peron, Yves Sznajer, Liesbeth De Waele, Anna Jansen, Marije Koopmans, Anneke Kievit, Laura S. Farach, Hope Northrup, Julian R. Sampson, Laura Thomas Orcid Logo, Wilfred F. J. van IJcken Orcid Logo

Human Mutation, Volume: 2023, Pages: 1 - 18

Swansea University Author: Laura Thomas Orcid Logo

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DOI (Published version): 10.1155/2023/4899372

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 i...

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Published in: Human Mutation
ISSN: 1098-1004
Published: Hindawi Limited 2023
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URI: https://cronfa.swan.ac.uk/Record/cronfa63881
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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.
Keywords: Tuberous sclerosis complex, TSC, TSC1, TSC2, inactivating variant
College: Faculty of Medicine, Health and Life Sciences
Funders: Financial support was provided by the Michelle Foundation (project number 1427012), the TSC Fonds (project number 111092), the TS Alliance (Award 06-16), and the TS Association UK (Award 2016-P07). L.G.D.d.A. was supported by a CAPES (Process: 88881.132401/2016-01; Brazil) scholarship. We acknowledge the support from the Wales Gene Park funded by the Welsh Government through Health and Care Research Wales.
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