title: Mosaicism for dominant collagen 6 mutations as a cause for intrafamilial phenotypic variability.
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.
authors.affiliation: National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neurogenetics Branch, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, Maryland, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Donkervoort
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Tanya
authors.initials: T
authors.lastname: Stojkovic
authors.forename: Nicol C
authors.initials: NC
authors.lastname: Voermans
authors.forename: A Reghan
authors.initials: AR
authors.lastname: Foley
authors.forename: Meganne E
authors.initials: ME
authors.lastname: Leach
authors.forename: Jahannaz
authors.initials: J
authors.lastname: Dastgir
authors.forename: Véronique
authors.initials: V
authors.lastname: Bolduc
authors.forename: Thomas
authors.initials: T
authors.lastname: Cullup
authors.forename: Alix
authors.initials: A
authors.lastname: de Becdelièvre
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.forename: Hai
authors.initials: H
authors.lastname: Su
authors.forename: Katherine
authors.initials: K
authors.lastname: Meilleur
authors.forename: Alice B
authors.initials: AB
authors.lastname: Schindler
authors.forename: Erik-Jan
authors.initials: EJ
authors.lastname: Kamsteeg
authors.forename: Pascale
authors.initials: P
authors.lastname: Richard
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Butterfield
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Winder
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Crawford
authors.forename: Robert B
authors.initials: RB
authors.lastname: Weiss
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Valérie
authors.initials: V
authors.lastname: Allamand
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D024142:Collagen Type VI / Q000235:genetics* / Q000378:metabolism; D003286:Contracture / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D009132:Muscles / Q000473:pathology*; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D012598:Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: C504344:COL6A2 protein, human; C000601102:COL6A3 protein, human; C553839:Col6a1 protein, human; D024142:Collagen Type VI
keywords: Bethlem myopathy; COL6A1; COL6A2; COL6A3; Ullrich congenital muscular dystrophy; collagen VI; genetic counseling