title: Correlation between fragment size at D4F104S1 and age at onset or at wheelchair use, with a possible generational effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD)
abstract: In facioscapulohumeral muscular dystrophy (FSHD), the wide range of clinical severity observed both within and between families has obscured past attempts to identify any phenotypic differences between families from which phenotype-genotype correlation could proposed, although it is noted that age at onset is youngest and severity greatest in isolated cases. From 14/16 large 4q35-linked FSHD families, and 25/34 isolated cases exhibiting a de novo D4F104S1 DNA fragment, we find a significant correlation between proband age at onset and FSHD-associated D4F104S1 fragment size (r = 0.56; p < 0.001), with the smallest fragments occurring in isolated cases. A similar correlation (r = 0.70; p < 0.01) with fragment size is observed for age to loss of ambulation in 16 subjects using a wheelchair. We find also that age at onset appears younger with successive generations in the 4q35 families. We propose that fragment size at D4F104S1, together with a possible generational effect, accounts for a significant part of the wide phenotypic variation in FSHD. Our results predict a more limited range for severity within families, and in one family with a 4q35-linked 38kb fragment support scapulohumeral presentation without facial involvement as a late onset variant of FSHD. We propose that in FSHD, quantitative variation in a uniform mutation mechanism influences age at onset, but by deletion rather than expansion of DNA.
authors.affiliation: Clinical Genetics Department, Bristol Childrens Hospital, UK.
authors.forename: P W
authors.initials: PW
authors.lastname: Lunt
authors.forename: P E
authors.initials: PE
authors.lastname: Jardine
authors.forename: M C
authors.initials: MC
authors.lastname: Koch
authors.forename: J
authors.initials: J
authors.lastname: Maynard
authors.forename: M
authors.initials: M
authors.lastname: Osborn
authors.forename: M
authors.initials: M
authors.lastname: Williams
authors.forename: P S
authors.initials: PS
authors.lastname: Harper
authors.forename: M
authors.initials: M
authors.lastname: Upadhyaya
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D002894:Chromosomes, Human, Pair 4; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D009136:Muscular Dystrophies / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D014910:Wheelchairs