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 s everity is greatest in isolated cases. From 14 of 16 large FSHD famili es 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 4 q35-linked 38-kb fragment in one family supports scapulohumeral presen tation without facial involvement as a milder late-onset variant of FS HD, and with apparent ''unaffected'' recombinants in smart families, s uggests that nonpenetrance is more likely with large fragment sizes. O ur results, predicting a more limited range for severity within famili es, and suggesting >85% of FSHD maps to 4q35, will facilitate genetic counseling. We propose that quantitative variation in a uniform mutati on mechanism influences age at onset, but by deletion rather than expa nsion of DNA. (C) 1995 John Wiley and Sons, Inc.