EVIDENCE FOR HETEROGENEITY IN FACIOSCAPULOHUMERAL MUSCULAR-DYSTROPHY (FSHD)

Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive primary disease of muscle which is usually inherited as an autosomal d ominant disorder. FSHD has been localized to the long arm of chromosom e 4, specifically to the 4q3.5-qter region. Initially published linkag e studies showed no evidence for heterogeneity in FSHD. In the present study we have examined individuals in seven FSHD families. Two-point lod scores show significant evidence for linkage for D4S163 (lod score 3.04 at recombination fraction .21) and D4S139 (lod score 3.84 at rec ombination fraction .20). D4S171 also gave a positive score (lod score 2.56 at recombination fraction .24). Significant evidence for heterog eneity was found for each of the three markers. Multipoint linkage ana lysis in this region resulted in a peak multipoint lod score of 6.47. The multipoint analysis supported the two-point studies with odds of 2 0:1 showing linkage and heterogeneity over linkage and homogeneity. Fi ve of the seven families gave a posterior probability of >95% of being of the linked type, while two families appeared unlinked to this regi on of 4q (P < .01%). Individuals in the two unlinked families met the clinical criteria for the diagnosis of FSHD, including facial weakness , clavicular flattening, scapula winging, proximal muscle weakness, an d myopathic changes on muscle biopsies without inflammatory or mitocho ndrial pathology. This study demonstrates genetic heterogeneity in FSH D and has important implications for both genetic counseling and the e lucidation of the etiology of FSHD.