4.6 Article

Low-level mosaicism in tuberous sclerosis complex: prevalence, clinical features, and risk of disease transmission

Journal

GENETICS IN MEDICINE
Volume 21, Issue 11, Pages 2639-2643

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/s41436-019-0562-6

Keywords

mosaicism; tuberous sclerosis complex; TSC1; TSC2; transmission risk

Funding

  1. Engles Family Fund for Research in TSC and LAM

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Purpose: To examine the prevalence and spectrum of mosaic variant allele frequency (MVAF) in tuberous sclerosis complex (TSC) patients with low-level mosaicism and correlate genetic findings with clinical features and transmission risk. Methods: Massively parallel sequencing was performed on 39 mosaic TSC patients with 170 different tissue samples. Results: TSC mosaic patients (MVAF: 0-10%, median 1.7% in blood DNA) had a milder and distinct clinical phenotype in comparison with other TSC series, with similar facial angiofibromas (92%) and kidney angiomyolipomas (83%), and fewer seizures, cortical tubers, and multiple other manifestations (p < 0.0001 for six features). MVAF of TSC1/TSC2 pathogenic variants was highly variable in different tissue samples. Remarkably, skin lesions were the most reliable tissue for variant identification, and 6 of 39 (15%) patients showed no evidence of the variant in blood. Semen analysis showed absence of the variant in 3 of 5 mosaic men. The expected distribution of MVAF in comparison with that observed here suggests that there is a considerable number of individuals with low-level mosaicism for a TSC2 pathogenic variant who are not recognized clinically. Conclusion: Our findings provide information on variability in MVAF and risk of transmission that has broad implications for other mosaic genetic disorders.

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