A new dosage test for subtelomeric 4;10 translocations improves conventional diagnosis of facioscapulohumeral muscular dystrophy (FSHD)

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the size reducti on of a polymorphic repeat array on 4q35. Probe p13E-11 recognises this chr omosomal rearrangement and is generally used for diagnosis. However, diagno sis of FSHD is complicated by three factors. First, the probe cross hybridi ses to a highly homologous repeat array locus on chromosome 10q26. Second, although a BlnI polymorphism allows discrimination between the repeat units on chromosomes 4 and 10 and greatly facilitates FSHD diagnosis, the occurr ence of translocations between chromosomes 4 and 10 further complicates acc urate FSHD diagnosis. Third, the recent identification of deletions of p13E -11 in both control and FSHD populations is an additional complicating fact or. Although pulsed field gel electrophoresis is very useful and sometimes necessary to detect these rearrangements, this technique is not operational in most FSHD diagnostic laboratories. Moreover, repeat arrays 2200 kb are often difficult to detect and can falsely suggest a deletion of p13E-11. Th erefore, me have developed an easy and reliable Southern blotting method to identify exchanges between 4 type and 10 type repeat arrays and deletions of p13E-11. This BglII-BlnI dosage test addresses all the above mentioned c omplicating factors and can be carried out in addition to the standard Sout hern blot analysis for FSHD diagnosis as performed in most laboratories. It will enhance the specificity and sensitivity of conventional FSHD diagnosi s to the values obtained by PFGE based diagnosis of FSHD. Moreover, this st udy delimits the FSHD candidate gene region by mapping the 4;10 translocati on breakpoint proximal to the polymorphic BlnI site in the first repeat uni t.