Mosaicism for dominant collagen 6 mutations as a cause for intrafamilial phenotypic variability

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. WeissFrancesco Muntoni, Valérie Allamand, Carsten G. Bönnemann

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)48-56
Number of pages9
JournalHuman mutation
Volume36
Issue number1
DOIs
StatePublished - Jan 1 2015

Keywords

  • Bethlem myopathy
  • COL6A1
  • COL6A2
  • COL6A3
  • Collagen VI
  • Genetic counseling
  • Ullrich congenital muscular dystrophy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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