Several years ago a transcriptional repressor was identified within the D4Z4 repeat array. However, we have recently demonstrated that overall, each D4Z4 repeat has an enhancer activity due to the presence of a very strong enhancer. Moreover, we have shown that a nuclear matrix attachment site, which is positioned in the immediate vicinity of the D4Z4 repeat array, may function as an insulator and block the D4Z4 enhancer in normal, but not FSHD, cells. In fact, this S/MAR is prominent in normal myoblasts and non-muscular human cells, and much weaker in muscle cells derived from FSHD patients. From this observation, we inferred that, in normal human myoblasts, the D4Z4 repeat array and neighboring genes are located in two distinct loops, whereas, in myoblasts from FSHD patients, they are in a single one. This suggests that a looping mechanism could lead to a direct contact between the D4Z4 array and genes that are positioned in cis on the chromosome but are too far away to be subjected to transcriptional regulation through classical molecular mechanisms. Intriguingly, FSHD occurs only in individuals bearing the 4qA allele. 4qA/B is a 10 kb-long polymorphic segment directly adjacent to the D4Z4 repeat array. It exists in two allelic forms, 4qA and 4qB, which are 92% identical and equally common in the general population. The main difference between the two alleles resides in a tract of b-satellite repeats present in 4qA but not 4qB. This dissimilarity may bear consequences either in the predisposition to deletions occurring within the D4Z4 repeat array or in the structural consequences of the deletion. Here, we have further investigated the three-dimensional structure of the 4q subtelomeric region using the recently described 3C technique. We now report significant differences existing between FSHD and normal muscle cells. Thus, the interactions detected by the 3C assays could have occurred in trans between chromosomes 4q and 10q rather than in cis within 4q. FSHD, however, has been reported to occur only in individuals with the 4qA allele.