Comprehensive genetic and phenotype analysis of 95 individuals with mosaic tuberous sclerosis complex

Katarzyna Klonowska; Krinio Giannikou; Joannes M Grevelink; Barbara Boeszoermenyi; Aaron R Thorner; Zachary T Herbert; Antara Afrin; Alison M Treichel; Lana Hamieh; Katarzyna Kotulska; Sergiusz Jozwiak; Joel Moss; Thomas N Darling; David J Kwiatkowski

doi:10.1016/j.ajhg.2023.04.002

Comprehensive genetic and phenotype analysis of 95 individuals with mosaic tuberous sclerosis complex

Am J Hum Genet. 2023 Jun 1;110(6):979-988. doi: 10.1016/j.ajhg.2023.04.002. Epub 2023 May 3.

Authors

Affiliations

¹ Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: kklonowska@bwh.harvard.edu.
² Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Hematology/Oncology, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
³ Boston Dermatology and Laser Center, Massachusetts General Hospital, Boston, MA 02114, USA.
⁴ Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁵ Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁶ Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁷ Department of Dermatology, Uniformed Services University, Bethesda, MA 20814, USA; Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁸ Department of Dermatology, Uniformed Services University, Bethesda, MA 20814, USA; Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Dermatology, University Hospitals Cleveland Medical Center, Case Western Reserve University Cleveland, Cleveland, OH 44106, USA.
⁹ Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Hospital Medicine, Barnes Jewish Hospital, Washington University in St Louis, St. Louis, MO 63110, USA.
¹⁰ Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw 04-736, Poland.
¹¹ Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw 04-736, Poland; Research Department, Children's Memorial Health Institute, Warsaw 04-736, Poland.
¹² Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
¹³ Department of Dermatology, Uniformed Services University, Bethesda, MA 20814, USA.
¹⁴ Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: dk@rics.bwh.harvard.edu.

Abstract

Tuberous sclerosis complex (TSC) is a neurogenetic disorder due to loss-of-function TSC1 or TSC2 variants, characterized by tumors affecting multiple organs, including skin, brain, heart, lung, and kidney. Mosaicism for TSC1 or TSC2 variants occurs in 10%-15% of individuals diagnosed with TSC. Here, we report comprehensive characterization of TSC mosaicism by using massively parallel sequencing (MPS) of 330 TSC samples from a variety of tissues and fluids from a cohort of 95 individuals with mosaic TSC. TSC1 variants in individuals with mosaic TSC are much less common (9%) than in germline TSC overall (26%) (p < 0.0001). The mosaic variant allele frequency (VAF) is significantly higher in TSC1 than in TSC2, in both blood and saliva (median VAF: TSC1, 4.91%; TSC2, 1.93%; p = 0.036) and facial angiofibromas (median VAF: TSC1, 7.7%; TSC2 3.7%; p = 0.004), while the number of TSC clinical features in individuals with TSC1 and TSC2 mosaicism was similar. The distribution of mosaic variants across TSC1 and TSC2 is similar to that for pathogenic germline variants in general TSC. The systemic mosaic variant was not present in blood in 14 of 76 (18%) individuals with TSC, highlighting the value of analysis of multiple samples from each individual. A detailed comparison revealed that nearly all TSC clinical features are less common in individuals with mosaic versus germline TSC. A large number of previously unreported TSC1 and TSC2 variants, including intronic and large rearrangements (n = 11), were also identified.

Keywords: TSC angiofibroma; TSC angiomyolipoma; TSC1; TSC2; low-level mosaicism; massively parallel sequencing; tuberous sclerosis complex; variant detection.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

MeSH terms

Humans
Mutation
Phenotype
Tuberous Sclerosis Complex 1 Protein / genetics
Tuberous Sclerosis Complex 2 Protein / genetics
Tuberous Sclerosis* / genetics
Tuberous Sclerosis* / pathology
Tumor Suppressor Proteins* / genetics

Substances

Tumor Suppressor Proteins
Tuberous Sclerosis Complex 2 Protein
Tuberous Sclerosis Complex 1 Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding