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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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spelling v2 63881 2023-07-14 Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal 6f80a1638d852bd88d37afe3aeb2fb62 0000-0002-8621-5285 Laura Thomas Laura Thomas true false 2023-07-14 BMS 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. Journal Article Human Mutation 2023 1 18 Hindawi Limited 1098-1004 Tuberous sclerosis complex, TSC, TSC1, TSC2, inactivating variant 13 7 2023 2023-07-13 10.1155/2023/4899372 http://dx.doi.org/10.1155/2023/4899372 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee 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. 2024-02-01T15:50:45.5682287 2023-07-14T09:10:22.1068427 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Hannah D. West 1 Mark Nellist 0000-0003-0949-1566 2 Rutger W. W. Brouwer 3 Mirjam C. G. N. van den Hout-van Vroonhoven 4 Luiz Gustavo Dufner de Almeida 5 Femke Hendriks 6 Peter Elfferich 7 Meera Raja 8 Peter Giles 9 Rosa M. Alfano 10 Angela Peron 11 Yves Sznajer 12 Liesbeth De Waele 13 Anna Jansen 14 Marije Koopmans 15 Anneke Kievit 16 Laura S. Farach 17 Hope Northrup 18 Julian R. Sampson 19 Laura Thomas 0000-0002-8621-5285 20 Wilfred F. J. van IJcken 0000-0002-0421-8301 21 63881__28364__04205ae7ca20420f965fe2380acf6d32.pdf 63881.VOR.pdf 2023-08-23T16:33:39.3743185 Output 1327312 application/pdf Version of Record true © 2023 Hannah D. West et al. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal
spellingShingle Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal
Laura Thomas
title_short Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal
title_full Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal
title_fullStr Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal
title_full_unstemmed Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal
title_sort Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal
author_id_str_mv 6f80a1638d852bd88d37afe3aeb2fb62
author_id_fullname_str_mv 6f80a1638d852bd88d37afe3aeb2fb62_***_Laura Thomas
author Laura Thomas
author2 Hannah D. West
Mark Nellist
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
Wilfred F. J. van IJcken
format Journal article
container_title Human Mutation
container_volume 2023
container_start_page 1
publishDate 2023
institution Swansea University
issn 1098-1004
doi_str_mv 10.1155/2023/4899372
publisher Hindawi Limited
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
url http://dx.doi.org/10.1155/2023/4899372
document_store_str 1
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description 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.
published_date 2023-07-13T15:50:46Z
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