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D4F104S1 deletion in facioscapulohumeral muscular dystrophy

Phenotype, size, and detection

From the Department of Human Genetics (Drs. Frants and van der Maarel, R.J.L.F. Lemmers), Center for Human and Clinical Genetics, Leiden University Medical Centre, and Department of Neurology (Dr. Padberg), University Medical Center Nijmegen, the Netherlands; Department of Molecular Immunology (Dr. Osborn), Babraham Institute, Cambridge, and Institute of Medical Genetics (Drs. Rogers, Cooper, and Upadhyaya), University of Wales College of Medicine, Cardiff, UK; and Max-Planck-Institut für Molekular Genetik (Dr. Haaf), Berlin, Germany.

Address correspondence and reprint requests to Dr. M. Upadhyaya, Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK, e-mail: upadhyaya{at}cardiff.ac.uk; or Dr. S. van der Maarel, Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Centre, Wassenaarseweg 72, 2333 AL Leiden, the Netherlands, e-mail: maarel@lumc.nl

Background: The facioscapulohumeral muscular dystrophy (FSHD) locus maps to 4q35 where it is closely linked to D4F104S1 (p13E-11), a probe that recognizes the pathognomonic FSHD deletion involving the subtelomeric D4Z4 tandem repeat array. Extended deletions that include both the more proximal D4F104S1 region and the D4Z4 repeat array proper do, however, occur, albeit rarely, and such deletions can lead to difficulties of interpretation in the diagnostic setting.

Objective: To devise a means to determine the true frequency of proximally extended deletions in individuals with FSHD.

Methods: Three families selected for this study were originally identified during routine FSHD analysis on the basis that the affected individuals in each family had failed to exhibit a small (<38-kb) EcoRI fragment. High molecular weight DNA from these families was analyzed with both conventional and pulsed-field gel electrophoresis using DNA markers p13E-11, 9B6A, B31, 4qA, and 4qB.

Results: Large genomic deletions were identified involving both D4Z4 and D4F104S1. The precise number of D4Z4 repeat units borne by the p13E11 deletion allele was established by the use of an additional restriction enzyme (MseI) digest. All three cases carry different sizes of deletion proximal to the D4Z4 repeat units. With use of a recently described telomeric probe, 4qA, a method was developed that identifies large genomic deletions involving both D4Z4 and D4F104S1 using conventional gel electrophoresis.

Conclusion: Proximally extended deletions can be found in patients with a normal spectrum of the disease. This assay promises to allow estimation of the true frequency of proximally extended deletions and should improve the accuracy and reliability of molecular diagnostic testing for FSHD.

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