Inheritance of a 38-kb fragment in apparently sporadic facioscapulohumeralmuscular dystrophy

Facioscapulohumeral dystrophy (FSHD) is an autosomal-dominant muscular diso rder associated with a short (<35 kb) EcoRI/BlnI fragment resulting from de letion of an integral number of units of a 3.3-kb repeat located at 4q35. I n this study, we determined fragment sizes separated by pulsed-field get el ectrophoresis in a patient with an apparently sporadic case of FSHD and in his healthy family members. A 38-kb fragment was detected in the proband, i n his older brother, and in their father. This finding prompted a clinical reevaluation of the father and brother. A subclinical phenotype restricted to abdominal muscle weakness was detected, and serum creatine kinase values were found to be elevated in both. The proband's brother also showed evide nce of an independently occurring subtelomeric rearrangement of 4q35, which normally occurs in about 20% of the population. The identification of a "b orderline" 38-kb EcoRI/BlnI fragment in an affected subject and his very mi ldly affected relatives extends the size range of disease alleles and expan ds existing data on the variable intrafamilial expressivity of FSHD. This s tudy highlights the importance of a careful molecular and clinical analysis extended to family members of apparently sporadic cases with larger EcoRI/ BlnI fragments for accurate diagnosis and appropriate genetic counseling in FSHD. (C) 1999 John Wiley & Sons, Inc.