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Genotype-phenotype study in an FSHD family with a proximal deletion encompassing p13E-11 and D4Z4

From the Center for Human Genetics (K.L.D., J.M.S., M.C.S., J.R.G.), Duke University Medical Center, Durham, NC; Center for Human and Clinical Genetics (R.J.L.F.L., R.K., R.R.F., S.M.vdM.), Leiden University Medical Center, Leiden, The Netherlands; Department of Neurology (R.T.), University of Rochester, Rochester, NY.

Address correspondence and reprint requests to Dr. John R. Gilbert, Duke University Medical Center, Box 3445, Durham, NC 27710; e-mail: john{at}chg.duhs.duke.edu

Background: In the majority of facioscapulohumeral muscular dystrophy (FSHD) cases, the molecular basis of the disease is due to loss of subtelomeric D4Z4 repeat units at 4q35. Occasionally, an apparent absence of the contracted D4Z4 repeat is associated with FSHD. One explanation for this finding is a deletion in the region proximal to the D4Z4 repeat array that encompasses the p13E-11 (D4F104S1) probe-binding site used in the DNA diagnosis. The frequency of such proximally extended deletions is unknown, and to date, few patients have been described due to the difficulties in the molecular identification of such cases.

Methods: We describe a family (DUK 2531) in which a contracted D4Z4 allele and a large proximal deletion of approximately 75 kb are segregating to 11 individuals. This is the largest deletion identified to date. Family DUK 2531 was initially thought to have normal D4Z4 fragment size and therefore unlinked to the 4q35 region (FSHD1B).

Results: Further molecular analysis of DUK 2531 reveals the presence of 10 repeat units (33 kb). The extended deletion includes the probe p13E-11 and B31 binding sites, the inverted repeat D4S2463, and genes FRG2 and TUBB4Q.

Conclusion: Despite the length of the proximal deletion in this family, the range and severity of the clinical manifestations are typical for the disorder. Because such deletions can lead to misinterpretation in the diagnostic setting, this suggests the need for additional diagnostic tests in facioscapulohumeral muscular dystrophy.

Editorial, see page 544

See also page 569

This article was previously published in electronic format as an Expedited E-Pub on January 17, 2007, at www.neurology.org.

Supported by grants from the FSH Society, the Muscular Dystrophy Association (United States), and the Shaw family (The Netherlands). R.T. is supported by the University of Rochester Paul D. Wellstone Muscular Dystrophy Cooperative Research Center (AR050762).

Disclosure: The authors report no conflicts of interest.

Received February 1, 2006. Accepted in final form November 27, 2006.

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