Elsevier

Neuromuscular Disorders

Volume 8, Issue 2, April 1998, Pages 126-130
Neuromuscular Disorders

Workshop report
44th ENMC International Workshop: Facioscapulohumeral Muscular Dystrophy: Molecular Studies: 19–21 July 1996, Naarden, The Netherlands

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Aims

The principal aim was:

  • (i) to collate data from each centre to determine the specificity and sensitivity of a potential diagnostic DNA test for FSHD.Other aims were:

  • (ii) to confirm correlation between phenotypic severity and genotype;

  • (iii) to assess the place of mosaicism in new mutation;

  • (iv) to document cases or families which are exceptions to the rules.

Background

FSHD is one of the most important neuromuscular disorders, demonstrating dominant inheritance and affecting 1/20 000 of the European population. The disease gene is not yet known, but in at least 80% of cases FSHD is associated with deletion of an integral number of copies of a tandemly repeated 3.3 kb sequence in a subtelomeric region at 4q35, producing a shortened DNA fragment detected by probe p13E-11 (locus D4F104S1) [1]. De novo cases of FSHD (which comprise 10% of all cases) are usually

Control data

Normal controls (622) had been studied by five groups, but unfortunately each group had chosen a different upper threshold size for classification of a `small' fragment (Table 1). Overall, 0/622 controls had DD fragments of <28kb, but 3/310 controls (1%) had DD fragments of <35 kb, and a probable higher proportion had fragments <38 kb. It was evident that there is a need for standardisation of the method for sizing fragments, particularly between 30 and 40 kb, where the standard error in

Conclusions of phenotype/genotype aspects

  • 1.

    The presence of a short (<35 kb) B1n-resistant fragment alone provides a diagnostic test for FSHD, for which the specificity and sensitivity are both high, but if combined additionally with PFGE, the specificity and sensitivity are improved even further.

  • 2.

    Recombinant cases (with p13E-11) or families unlinked to 4q35 comprise only a very small proportion of all cases.

  • 3.

    Around 20% of new mutation cases may arise from mosaicism in one parent, but a further 12% may be due to parental non-penetrance or

Use of polymerase chain reaction (PCR)

Current genetic testing with p13E-11 uses Southern blot techniques. Arahata presented a PCR technique which uses primers for chromosome 4-specific sequences flanking the total 3.3 kb repeats, and can amplify up to four repeats (equivalent to an approximately 23 kb fragment on Southern blotting). Therefore only the repeats at 4q35 are seen. Additionally, use of B1nI determines whether the repeats are of chromosome 4-type or chromosome 10-type (or a hybrid of both). At present the technique is

Efforts at gene cloning

The 3.3 kb repeat does not contain an open-reading frame and any mRNA produced is assumed not to be translated. Jane Hewitt had cloned the telomeric region beyond the 3.3 kb repeats, but this has proved to have a lot of repeat sequences which cross-hybridize with chromosomes 14,22 and other acrocentrics, but does not exhibit open reading frames. One gene (FRG1) mapping proximal to the 3.3 kb repeats had already been cloned by van Deutekom [5]. Sequencing of the coding region in a typical FSHD

List of participants

Sponsored and hosted by the European Neuromuscular Centre (ENMC), this workshop brought together 18 participants from 9 European groups and one from Japan who form part of the International Working Group involved in researching the molecular basis of facioscapulohumeral muscular dystrophy (FSHD).

K. Arahata (Tokyo, Japan)

E. Bakker (Leiden, The Netherlands)

O. Brouwer (Leiden, The Netherlands)

C. de Toma (Paris, France)

G. Deidda (Rome, Italy)

L. Felicetti (Rome, Italy)

R. Frants (Leiden, The

Acknowledgements

We are grateful to ENMC for financial support and to Professor Alan Emery (Research Director of ENMC) for his scientific advice and Mr. M. Rutgers and Ms. Janine de Vries for organisational help. This Workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and ENMC main sponsors: Association Française contre les Myopathies (France); Italian Telethon Committee (Italy); Muscular Dystrophy Group of Great Britain and Northern Ireland (UK); Vereniging

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