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Imaging Features of Systemic Sclerosis-Associated Interstitial Lung Disease
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Low-level mosaicism in tuberous sclerosis complex: prevalence, clinical features, and risk of disease transmission
Krinio Giannikou1, Kathryn D Lasseter1, Joannes M Grevelink2
1Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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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