Krinio Giannikou1, Kathryn D Lasseter1, Joannes M Grevelink2, Magdalena E Tyburczy1, Kira A Dies3, Zachary Zhu1, Lana Hamieh1, Bruce M Wollison4, Aaron R Thorner4, Stephen J Ruoss5, Elizabeth A Thiele6, Mustafa Sahin3, David J Kwiatkowski7. 1. Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 2. Boston Dermatology and Laser Center, Massachusetts General Hospital, Boston, MA, USA. 3. Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. 4. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA. 5. Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA, USA. 6. Department of Neurology, Massachusetts General Hospital, Boston and Harvard Medical School, Boston, MA, USA. 7. Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. dk@rics.bwh.harvard.edu.
Abstract
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.
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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Authors: Krinio Giannikou; Zachary Zhu; Jaegil Kim; Kellen D Winden; Magdalena E Tyburczy; David Marron; Joel S Parker; Zachary Hebert; Anika Bongaarts; Len Taing; Henry W Long; William V Pisano; Sanda Alexandrescu; Brianna Godlewski; Mark Nellist; Katarzyna Kotulska; Sergiusz Jozwiak; Marcin Roszkowski; Marek Mandera; Elizabeth A Thiele; Hart Lidov; Gad Getz; Orrin Devinsky; Michael S Lawrence; Keith L Ligon; David W Ellison; Mustafa Sahin; Eleonora Aronica; David M Meredith; David J Kwiatkowski Journal: Mod Pathol Date: 2020-10-13 Impact factor: 8.209
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