Mosaicism for Dominant Collagen 6 Mutations as a Cause for Intrafamilial Phenotypic Variability
Year: 2014
Type: article
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.
Source: Human Mutation
DOI: 10.1002/humu.22691
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
Institutions: National Institutes of Health, National Institute of Neurological Disorders and Stroke, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Radboud University Medical Center, Great Ormond Street Hospital, University College London, Children's National, Guy's Hospital, University of Florida, National Institute of Nursing Research, Fondation pour l’innovation en Cadiométabolisme et Nutrition, Université Pierre-et-Marie-Curie, University of Utah, Marshfield Clinic, Johns Hopkins University, Johns Hopkins Medicine, Centre National de la Recherche Scientifique, Inserm, Institut de Myologie
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1963870013