A comparative analysis of RAS variants in patients with disorders of somatic mosaicism |
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| Institution: | 1. Department of Pathology & Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO;2. Clinical Laboratory, Phoenix Children’s Hospital, Phoenix, AZ;3. Departments of Pediatrics and Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL;4. Division of Dermatology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL;5. Division of Pediatric Surgery, Department of Surgery, University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, CO;6. Division of Medical Genetics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA;7. Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, Washington University, St. Louis, MO;8. Division of Dermatology, Departments of Medicine and Pediatrics, Washington University School of Medicine, St. Louis, MO;9. Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO;10. Department of Pediatric Plastic and Reconstructive Surgery, Nationwide Children’s Hospital, Columbus, OH;11. Division of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children’s Hospital, Columbus, OH;12. Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH;13. Genetic Medicine Service, Montreal University Hospital (CHUM-CRCHUM), Montréal, Quebec, Canada;14. Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH;15. Department of Pathology, The Ohio State University College of Medicine, Columbus, OH;16. Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO;1. Autism & Developmental Medicine Institute, Geisinger, Lewisburg, PA;2. Department of Genomic Health, Geisinger, Danville, PA;1. Division of Pediatric Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics, University of Michigan Health System, University of Michigan, Ann Arbor, MI;1. Genetics and Metabolism, University of Tennessee Health Science Center, LeBonheur Children’s Hospital, Memphis, TN;2. Pathology and Laboratory Medicine, Children’s National Hospital, Washington, DC;3. Genetics and Metabolism, Rare Disease Institute, Children’s National Hospital, Washington, DC;4. Department of Pathology, Stanford University School of Medicine, Stanford, CA;1. Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC;2. Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA;3. Stanford Center for Undiagnosed Diseases, Stanford University, and Department of Pediatrics, Stanford University School of Medicine, Stanford, CA;4. Institute for Genome Medicine, Columbia University Medical Center, New York, NY;1. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, United Kingdom;2. MRC Human Genetics Unit, Institute of Genetic and Cancer, The University of Edinburgh, Edinburgh, United Kingdom;3. National Heart and Lung Institute and MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom;4. Center for Genomic Medicine, Massachusetts General Hospital and Broad Institute of MIT and Harvard, Boston, MA;5. East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom;6. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom;1. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada;2. Genomics Health Services and Policy Research Program, Li Ka Shing Knowledge Institute, St. Michael''s Hospital, Unity Health Toronto, Toronto, Ontario, Canada;3. Lunenfeld Tanenbaum Research Institute, Sinai Health, Toronto, Ontario, Canada;4. Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, Ontario, Canada;5. Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada;6. Li Ka Shing Knowledge Institute, St. Michael''s Hospital, Unity Health Toronto, Toronto, Ontario, Canada;7. Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada;8. Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia;9. Ontario Institute for Cancer Research, Toronto, Ontario, Canada |
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| Abstract: | PurposeRAS genes (HRAS, KRAS, and NRAS) are commonly found to be mutated in cancers, and activating RAS variants are also found in disorders of somatic mosaicism (DoSM). A survey of the mutational spectrum of RAS variants in DoSM has not been performed.MethodsA total of 938 individuals with suspected DoSM underwent high-sensitivity clinical next-generation sequencing?based testing. We investigated the mutational spectrum and genotype?phenotype associations of mosaic RAS variants.ResultsIn this article, we present a series of individuals with DoSM with RAS variants. Classic hotspots, including Gly12, Gly13, and Gln61 constituted the majority of RAS variants observed in DoSM. Furthermore, we present 12 individuals with HRAS and KRAS in-frame duplication/insertion (dup/ins) variants in the switch II domain. Among the 18.3% individuals with RAS in-frame dup/ins variants, clinical findings were mainly associated with vascular malformations. Hotspots were associated with a broad phenotypic spectrum, including vascular tumors, vascular malformations, nevoid proliferations, segmental overgrowth, digital anomalies, and combinations of these. The median age at testing was higher and the variant allelic fraction was lower in individuals with in-frame dup/ins variants than those in individuals with mosaic RAS hotspots.ConclusionOur work provides insight into the allelic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions. |
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| Keywords: | Disorders of somatic mosaicism In-frame insertions |
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