INTERCHROMOSOMAL AND INTRACHROMOSOMAL SUB-TELOMERIC REARRANGEMENTS ON4Q35 - IMPLICATIONS FOR FACIOSCAPULOHUMERAL MUSCULAR-DYSTROPHY (FSHD)ETIOLOGY AND DIAGNOSIS

The autosomal dominant myopathy facioscapulohumeral muscular dystrophy (FSHD) is causally related to a short EcoRI fragment detected by prob e p13E-11, This remnant fragment is the result of a deletion of an int egral number of tandemly arrayed 3.3 kb repeat units (D4Z4) on 4q35, D espite intensive efforts, no transcribed sequences have been identifie d within this array. Previously, we have shown that these repeats on 4 q35 have been exchanged for a similar highly homologous repeat locus o n 10q26 in 20% of the population and that a short chromosome 10-like a rray on 4q35 also results in FSHD, Here, we describe the hybrid struct ure of some of these repeat arrays, reflecting additional sub-telomeri c instability, In three healthy individuals carrying a 4-like repeat o n chromosome 10 or vice versa, one repeat array was shown to consist o f hybrid clusters of 4-derived and 10-derived repeat units. Moreover, employing pulsed field gel electrophoresis analysis, we identified two unrelated individuals carrying deletions of a chromosomal segment (p1 3E-11) proximal to the repeat locus, These deletions were not associat ed with FSHD, In one of these cases, however, an expansion of the dele tion into the repeat array was observed in one of his children sufferi ng from FSHD, These data provide additional evidence for instability o f this sub-telomeric region and suggests that the length of the repeat , and not its intrinsic properties, is crucial to FSHD, Moreover, they are in agreement with the hypothesis that FSHD is caused by a positio n effect in which the repeat structure influences the expression of ge nes nearby. Therefore, the region deleted proximal to the repeat locus in healthy individuals can be instrumental to refine the critical reg ion for FSHD1.