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

Authors

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 E Thomas
Wilfred F J van IJcken

Language

English

Publication Date

1-1-2023

Journal

Human Mutation

DOI

10.1155/2023/4899372

PMID

40225170

PMCID

PMC11918493

PubMedCentral® Posted Date

7-13-2023

PubMedCentral® Full Text Version

Post-print

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

Humans, Tuberous Sclerosis Complex 2 Protein, Tuberous Sclerosis, Tuberous Sclerosis Complex 1 Protein, High-Throughput Nucleotide Sequencing, Genetic Testing, Female, Male, Mosaicism, Mutation, Genetic Predisposition to Disease, Adult, Genomics, Child, Adolescent, Genetic Variation

Published Open-Access

yes

Recommended Citation

West, Hannah D; Nellist, Mark; Brouwer, Rutger W W; et al., "Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal" (2023). Faculty, Staff and Student Publications. 5628.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5628