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Updated: Jul 4, 2026
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Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Molecular Diagnosis in Patients With Tuberous Sclerosis Complex: A Deep Sequencing Approach in Clinical Practice
Joana A Neto1, Jacinta Fonseca1, Cláudia Melo1
1Pediatric Neurology Unit, Department of Pediatrics, Hospital de São João, Porto, PRT.
Cureus
|July 3, 2026
Summary
High-depth sequencing successfully diagnosed tuberous sclerosis complex (TSC) in over half of previously unsolved cases by identifying deep intronic variants in the TSC2 gene. This advanced genetic testing improves diagnosis and genetic counseling for TSC patients.
Area of Science:
- Genetics
- Neurocutaneous Disorders
- Molecular Diagnostics
Background:
- Tuberous sclerosis complex (TSC) is an inherited disorder affecting multiple organs.
- Conventional genetic testing often fails to identify the cause in some TSC patients.
- Deep intronic variants, structural anomalies, and mosaicism are potential reasons for diagnostic challenges.
Purpose of the Study:
- To evaluate the diagnostic utility of high-depth next-generation sequencing (NGS) in patients with unsolved TSC.
- To identify pathogenic variants missed by conventional genetic screening methods.
Main Methods:
- Retrospective analysis of seven patients with unsolved TSC after standard genetic testing.
- Application of high-depth targeted NGS (median depth ≥800×).
- Correlation of genetic findings with clinical phenotype.
Main Results:
- High-depth NGS identified pathogenic TSC2 variants in 57.1% (4/7) of previously unresolved cases.
- Identified variants included deep intronic structural alterations and splice-modifying changes.
- Patients with identified TSC2 variants showed a higher prevalence of CNS anomalies, epilepsy, and tumors.
Conclusions:
- High-depth targeted sequencing significantly increases the diagnostic yield for TSC, particularly for deep intronic variants.
- Integrating deep sequencing into clinical practice is recommended for unsolved TSC cases.
- Molecular diagnosis aids in genetic counseling and potential targeted therapy access.
