CORRELATION BETWEEN FRAGMENT SIZE AT D4F104S1 AND AGE AT ONSET OR AT WHEELCHAIR USE, WITH A POSSIBLE GENERATIONAL-EFFECT, ACCOUNTS FOR MUCHPHENOTYPIC VARIATION IN 4Q35-FACIOSCAPULOHUMERAL MUSCULAR-DYSTROPHY (FSHD)

In facioscapulohumeral muscular dystrophy (FSHD), the wide range of cl inical severity observed both within and between families has obscured past attempts to identify any phenotypic differences between families from which phenotype-genotype correlation could be proposed, although it is noted that age at onset is youngest and severity greatest in is olated cases, From 14/16 large 4q35-linked FSHD families, and 25/34 is olated cases exhibiting a de novo D4F104S1 DNA fragment, we find a sig nificant correlation between proband age at onset and FSHD-associated D4F104S1 fragment size (r = 0.56; p < 0.001), with the smallest fragme nts 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 variati on in FSHD, Our results predict a more limited range for severity with in families, and in one family with a 4q35-linked 38kb fragment suppor t scapulohumeral presentation without facial involvement as a late ons et 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.