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Mosaicism for Dominant Collagen 6 Mutations as a Cause for Intrafamilial Phenotypic Variability
Author(s) -
Donkervoort Sandra,
Hu Ying,
Stojkovic Tanya,
Voermans Nicol C.,
Foley A. Reghan,
Leach Meganne E.,
Dastgir Jahannaz,
Bolduc Véronique,
Cullup Thomas,
Becdelièvre Alix,
Yang Lin,
Su Hai,
Meilleur Katherine,
Schindler Alice B.,
Kamsteeg ErikJan,
Richard Pascale,
Butterfield Russell J.,
Winder Thomas L.,
Crawford Thomas O.,
Weiss Robert B.,
Muntoni Francesco,
Allamand Valérie,
Bönnemann Carsten G.
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22691
Subject(s) - biology , genetics , collagen vi , penetrance , germline mosaicism , phenotype , allele , expressivity , heterozygote advantage , compound heterozygosity , genetic heterogeneity , nonsense mutation , allelic heterogeneity , epidermolysis bullosa simplex , mutation , epidermolysis bullosa , missense mutation , gene
Collagen 6‐related dystrophies and myopathies ( COL 6‐ RD ) are a group of disorders that form a wide phenotypic spectrum, ranging from severe U llrich congenital muscular dystrophy, intermediate phenotypes, to the milder B ethlem myopathy. Both inter‐ and intrafamilial variable expressivity are commonly observed. We present clinical, immunohistochemical, and genetic data on four COL 6‐ 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 ( COL 6 A 1 , COL 6 A 2 , and COL 6 A 3 ) 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 COL 6‐ RD , and suggests that sporadic and parental mosaicism may be more common than previously suspected.