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Mosaicism in tuberous sclerosis complex: Lowering the threshold for clinical reporting
Zimeng Ye1, Sufang Lin2, Xia Zhao2
1Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Heidelberg, Victoria, Australia.
Human Mutation
|August 28, 2022
Summary
Low-level mosaic mutations in TSC1/TSC2 genes are often missed in tuberous sclerosis complex (TSC) genetic testing. Implementing sensitive assays can significantly improve diagnosis rates for TSC patients and families.
Area of Science:
- Genetics
- Molecular Biology
- Medical Diagnostics
Background:
- Tuberous sclerosis complex (TSC) is a genetic disorder affecting multiple organ systems.
- Routine genetic testing for TSC1/TSC2 mutations fails to identify causative variants in 10%-15% of patients.
- This diagnostic gap suggests the presence of undetected genetic alterations, such as low-level mosaicism.
Purpose of the Study:
- To investigate the role of low-level mosaic TSC1/TSC2 mutations in patients with unexplained TSC.
- To assess the prevalence of parental mosaicism in families with suspected TSC inheritance.
- To evaluate the diagnostic yield of enhanced genetic testing methods for TSC.
Main Methods:
- Deep panel sequencing was employed for 31 sporadic TSC patients and 8 families with suspected parental mosaicism.
- Droplet digital polymerase chain reaction (ddPCR) was used for sensitive variant detection.
- Analysis focused on identifying low-level mosaic TSC1/TSC2 variants missed by standard clinical genetic testing.
Main Results:
- Pathogenic variants were identified in 71% (22/31) of previously unsolved sporadic TSC patients.
- Of these, 16 patients had mosaic mutations (median VAF 6.8% in blood), and 6 had missed germline mutations.
- Parental mosaicism was detected in 5 out of 8 families (median VAF 1% in blood).
Conclusions:
- Low-level mosaic TSC1/TSC2 mutations contribute significantly to the diagnostic challenges in tuberous sclerosis complex.
- Current clinical genetic testing thresholds (typically >10% VAF) miss a substantial number of pathogenic variants.
- Implementing higher sensitivity assays is crucial for improving TSC diagnostic yield, patient management, and reproductive counseling.
