G.P.214: Mosaicism for dominant COLVI mutations as a cause for intra-familial phenotypic variability

Abstract

Collagen VI-related dystrophies and myopathies (COL6-RD) are a highly variable group of disorders that form a phenotypic spectrum ranging from severe Ullrich congenital muscular dystrophy (UCMD) via intermediate phenotypes to the milder Bethlem myopathy (BM). Both inter- and intra-familial variable expressivity of severity are commonly observed. We present clinical, immunohistochemical, and genetic data on four families with marked inter-generational phenotypic variability masquerading as anticipation due to parental mosaicism for a dominant mutation, with subsequent full inheritance and penetrance of the mutation in the heterozygous offspring. Additionally, we present a 5th 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 in genomic DNA from various tissues; including blood, saliva, and dermal fibroblasts. Consistent with somatic mosaicism parental samples had lower ratios of mutant versus wild type allele compared to the fully heterozygote offspring, although there was notable variability of the mutant 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 intra-familial/inter-generational variability of COL6-RD, suggesting that sporadic and parental mosaicism may be more common than previously suspected.