A new dosage test for subtelomeric 4;10 translocations improves conventional diagnosis of facioscapulohumeral muscular dystrophy (FSHD)
Silvère M van der Maarela, Giancarlo Deidda* b, Richard J L F Lemmersa, Egbert Bakkera, Michiel J R van der Wielena, Lodewijk Sandkuijla, Jane E Hewitt
c, George W Padbergd, Rune R Frantsa
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
* 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.
© 1999 by J Med Genet
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