Mosaicism for Dominant Collagen 6 Mutations as a Cause for Intrafamilial Phenotypic Variability |
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| Authors: | Sandra Donkervoort Ying Hu Tanya Stojkovic Nicol C. Voermans A. Reghan Foley Meganne E. Leach Jahannaz Dastgir Véronique Bolduc Thomas Cullup Alix de Becdelièvre Lin Yang Hai Su Katherine Meilleur Alice B. Schindler Erik‐Jan Kamsteeg Pascale Richard Russell J. Butterfield Thomas L. Winder Thomas O. Crawford Robert B. Weiss Francesco Muntoni Valérie Allamand Carsten G. Bönnemann |
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| Affiliation: | 1. National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neurogenetics Branch, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, Maryland, USA;2. AP‐HP, H?pitaux universitaires la Pitié‐Salpêtrière‐Charles Foix, Centre de Référence de Pathologie Neuromusculaire Paris Est, Paris, France;3. Department of Neurology, Radboud university medical center, Nijmegen, The Netherlands;4. Dubowitz Neuromuscular Centre, University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK;5. Children's National association: Children's National Health System, Washington, DC;6. DNA Laboratory, GSTS Pathology, Guy's Hospital, London, UK;7. AP‐HP, H?pitaux Universitaires La Pitié Salpêtrière – Charles Foix, U.F. Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Service de Biochimie Métabolique, Paris, France;8. Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA;9. National Institute of Nursing Research, Bethesda, Maryland, USA;10. Department of Human Genetics, Genome Diagnostics, Radboud university medical centre, Nijmegen, The Netherlands;11. UMR_S 1166 Equipe Génomique et Physiopathologie des Maladies Cardiovasculaires, Paris, France;12. UPMC, IFR14, Institute of Cardiometabolism and Nutrition, Paris, France;13. Department of Neurology and Pediatrics, University of Utah, Salt Lake City, Utah;14. Prevention Genetics, Marshfield, Wisconsin;15. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland;16. Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA;17. Sorbonne Universités, UPMC University, Paris, France;18. Inserm, U974, Paris, France;19. CNRS, UMR7215, Paris, France;20. Institut de Myologie, Paris, France |
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| Abstract: | Collagen 6‐related dystrophies and myopathies (COL6‐RD) are a group of disorders that form a wide phenotypic spectrum, ranging from severe Ullrich congenital muscular dystrophy, intermediate phenotypes, to the milder Bethlem myopathy. Both inter‐ and intrafamilial variable expressivity are commonly observed. We present clinical, immunohistochemical, and genetic data on four COL6‐RD families with marked intergenerational phenotypic heterogeneity. This variable expression seemingly masquerades as anticipation is due to parental mosaicism for a dominant mutation, with subsequent full inheritance and penetrance of the mutation in the heterozygous offspring. We also present an additional fifth simplex patient identified as a mosaic carrier. Parental mosaicism was confirmed in the four families through quantitative analysis of the ratio of mutant versus wild‐type allele (COL6A1, COL6A2, and COL6A3) in genomic DNA from various tissues, including blood, dermal fibroblasts, and saliva. Consistent with somatic mosaicism, parental samples had lower ratios of mutant versus wild‐type allele compared with the fully heterozygote offspring. However, there was notable variability of the mutant allele levels between tissues tested, ranging from 16% (saliva) to 43% (fibroblasts) in one mosaic father. This is the first report demonstrating mosaicism as a cause of intrafamilial/intergenerational variability of COL6‐RD, and suggests that sporadic and parental mosaicism may be more common than previously suspected. |
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| Keywords: | COL6A1 COL6A2 COL6A3 collagen VI genetic counseling Bethlem myopathy Ullrich congenital muscular dystrophy |
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