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J Med Genet 1999;36:823-828 ( November )

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

Silvère M van der Maarel^a, Giancarlo Deidda^{* b}, Richard J L F Lemmers^a, Egbert Bakker^a, Michiel J R van der Wielen^a, Lodewijk Sandkuijl^a, Jane E Hewitt ^c, George W Padberg^d, Rune R Frants^a

^a MGC-Department of Human Genetics, Leiden University Medical Centre, Wassenaarseweg 72, 2300 RA Leiden, The Netherlands, ^b Institute of Cell Biology, CNR, Rome, Italy, ^c School of Biological Sciences, University of Manchester, Manchester, UK, ^d Department of Neurology, University Hospital Nijmegen, Nijmegen, The Netherlands

Correspondence to: Dr van der Maarel.

Revised version received 8 June 1999; Accepted for publication 21 July 1999

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the size reduction of a polymorphic repeat array on 4q35. Probe p13E-11 recognises this chromosomal rearrangement and is generally used for diagnosis. However, diagnosis of FSHD is complicated by three factors. First, the probe cross hybridises 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 occurrence of translocations between chromosomes 4 and 10 further complicates accurate FSHD diagnosis. Third, the recent identification of deletions of p13E-11 in both control and FSHD populations is an additional complicating factor. 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 >200 kb are often difficult to detect and can falsely suggest a deletion of p13E-11. Therefore, we 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 complicating factors and can be carried out in addition to the standard Southern blot analysis for FSHD diagnosis as performed in most laboratories. It will enhance the specificity and sensitivity of conventional FSHD diagnosis to the values obtained by PFGE based diagnosis of FSHD. Moreover, this study delimits the FSHD candidate gene region by mapping the 4;10 translocation breakpoint proximal to the polymorphic BlnI site in the first repeat unit.


Keywords: FSHD; diagnosis; dosage; subtelomere

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^* Present address: MGC-Department of Human Genetics, Leiden University Medical Centre, The Netherlands.

Present address: Division of Genetics, Queen's Medical Centre, Nottingham University, Nottingham, UK.

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© 1999 by J Med Genet

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