Phenotypic-genotypic correlation will assist genetic counseling in 4q35-facioscapulohumeral muscular dystrophy

The wide range of severity in facioscapulohumeral muscular dystrophy (FSHD) complicates genetic advice, although onset age is youngest and severity is greatest in isolated cases. From 14 of 16 large FSHD families which are 4q35 linked, and from 25 of 34 isolated cases exhibiting a de novo D4F104S1 DNA fragment, we find a 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 4q35-linked 38-kb fragment in one family supports scapulohumeral presentation without facial involvement as a milder late-onset variant of FSHD, and with apparent "unaffected" recombinants in small families, suggests that nonpenetrance is more likely with large fragment sizes. Our results, predicting a more limited range for severity within families, and suggesting > 85% of FSHD maps to 4q35, will facilitate genetic counseling. We propose that quantitative variation in a uniform mutation mechanism influences age at onset, but by deletion rather than expansion of DNA.