Dataset Information

Targeted Next Generation Sequencing reveals previously unidentified TSC1 and TSC2 mutations.

ABSTRACT:

Background

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in TSC1 and TSC2. Conventional DNA diagnostic screens identify a TSC1 or TSC2 mutation in 75 - 90% of individuals categorised with definite TSC. The remaining individuals either have a mutation that is undetectable using conventional methods, or possibly a mutation in another as yet unidentified gene.

Methods

Here we apply a targeted Next Generation Sequencing (NGS) approach to screen the complete TSC1 and TSC2 genomic loci in 7 individuals fulfilling the clinical diagnostic criteria for definite TSC in whom no TSC1 or TSC2 mutations were identified using conventional screening methods.

Results

We identified and confirmed pathogenic mutations in 3 individuals. In the remaining individuals we identified variants of uncertain clinical significance. The identified variants included mosaic changes, changes located deep in intronic sequences and changes affecting promoter regions that would not have been identified using exon-only based analyses.

Conclusions

Targeted NGS of the TSC1 and TSC2 loci is a suitable method to increase the yield of mutations identified in the TSC patient population.

SUBMITTER: Nellist M

PROVIDER: S-EPMC4422413 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Publications

Targeted Next Generation Sequencing reveals previously unidentified TSC1 and TSC2 mutations.

Nellist Mark M Brouwer Rutger W W RW Kockx Christel E M CE van Veghel-Plandsoen Monique M Withagen-Hermans Caroline C Prins-Bakker Lida L Hoogeveen-Westerveld Marianne M Mrsic Alan A van den Berg Mike M P MM Koopmans Anna E AE de Wit Marie-Claire MC Jansen Floor E FE Maat-Kievit Anneke J A AJ van den Ouweland Ans A Halley Dicky D de Klein Annelies A van IJcken Wilfred F J WF

BMC medical genetics 20150225

<h4>Background</h4>Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in TSC1 and TSC2. Conventional DNA diagnostic screens identify a TSC1 or TSC2 mutation in 75 - 90% of individuals categorised with definite TSC. The remaining individuals either have a mutation that is undetectable using conventional methods, or possibly a mutation in another as yet unidentified gene.<h4>Methods</h4>Here we apply a targeted Next Generation Sequencing (NGS) approach to screen ...[more]

PMID: 25927202

Similar Datasets

Project description:BackgroundWith the expanded availability of next generation sequencing (NGS)-based clinical genetic tests, clinicians seeking to test patients with Mendelian diseases must weigh the superior coverage of targeted gene panels with the greater number of genes included in whole exome sequencing (WES) when considering their first-tier testing approach. Here, we use an in silico analysis to predict the analytic sensitivity of WES using pathogenic variants identified on targeted NGS panels as a reference.MethodsCorresponding nucleotide positions for 1533 different alterations classified as pathogenic or likely pathogenic identified on targeted NGS multi-gene panel tests in our laboratory were interrogated in data from 100 randomly-selected clinical WES samples to quantify the sequence coverage at each position. Pathogenic variants represented 91 genes implicated in hereditary cancer, X-linked intellectual disability, primary ciliary dyskinesia, Marfan syndrome/aortic aneurysms, cardiomyopathies and arrhythmias.ResultsWhen assessing coverage among 100 individual WES samples for each pathogenic variant (153,300 individual assessments), 99.7% (n = 152,798) would likely have been detected on WES. All pathogenic variants had at least some coverage on exome sequencing, with a total of 97.3% (n = 1491) detectable across all 100 individuals. For the remaining 42 pathogenic variants, the number of WES samples with adequate coverage ranged from 35 to 99. Factors such as location in GC-rich, repetitive, or homologous regions likely explain why some of these alterations were not detected across all samples. To validate study findings, a similar analysis was performed against coverage data from 60,706 exomes available through the Exome Aggregation Consortium (ExAC). Results from this validation confirmed that 98.6% (91,743,296/93,062,298) of pathogenic variants demonstrated adequate depth for detection.ConclusionsResults from this in silico analysis suggest that exome sequencing may achieve a diagnostic yield similar to panel-based testing for Mendelian diseases.

Dataset Information

Targeted Next Generation Sequencing reveals previously unidentified TSC1 and TSC2 mutations.

Background

Methods

Results

Conclusions

Publications

Targeted Next Generation Sequencing reveals previously unidentified TSC1 and TSC2 mutations.

Similar Datasets

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