The FSH Society receives numerous inquiries about understanding genetic test results.

The following excerpts are from Deymeer F (ed): Neuromuscular Diseases: From Basic Mechanisms to Clinical Management. Clin Neurosci. Basel, Karger, 2000. vol 18. pp 44-60. The chapter title Facioscapulohumeral Muscular Dystrophy: Diagnostic and Molecular Aspects is by Peter Lunt, Ph.D., Clinical Genetics Unit, Bristol Royal Hospital for Sick Children, Bristol, UK.

Pages 48-49 have a section headed Molecular Testing: Confirmation of Diagnosis that states: In 90-95% of cases of FSHD, as defined by meeting the diagnostic criteria, the diagnosis can effectively be confirmed by showing the presence of a shortened (<35 kb) DNA fragment at 4q35 (recognized by probe pl3E-11), which arises from deletion of an integral number of copies of the 3.3-kb repeats from that region. The DNA probe used (pl3E-11) also detects the closely homologous 3.3-kb repeat array from 10q26. However, each chromosome 10-type repeat has an additional BlnI restriction site. For the specific diagnostic test, a double digest with EcoRi/BlnI is employed on genomic DNA (obtained from peripheral blood), which removes chromosome 10-type repeats, but leaves chromosome 4-type repeats intact (albeit reduced by 3 kb in size compared to EcoR1 single digest) {Source: Neuromuscular Diseases: From Basic Mechanisms to Clinical Management.Chapter p 48-49 Facioscapulohumeral Muscular Dystrophy: Diagnostic and Molecular Aspects, by Peter Lunt, Ph.D.]

Page 45 of the chapter defines the generally accepted correlation between clinical severity and D4Z4 repeat number calculation. It is found that the age at onset and severity of clinical presentation correlates broadly and inversely with the size of the residual DNA fragment at 4q35, and, by inference, therefore correlates directly with the number of repeat units deleted. Thus, the smallest residual fragment lengths at 10-17 kb (1-3 repeat copies) are usually associated with a severe infantile or childhood presentation, medium lengths (18 30 kb, or 4-7 repeat copies) are often found in the largest recognised dominant families, while the largest lengths (31-38 kb, or 8-10 repeat copies) have been associated with a milder predominantly scapulohumeral presentation and may well have reduced penetrance, particularly in females. New mutation cases are seen predominantly with the smallest residual fragment lengths, giving matching clinical severity, and may originate predominantly on the maternal copy of chromosome 4. Study of parental DNA suggests that around 20-30% of new mutations occur as somatic and germline events in one of the parents, this usually also being the mother.

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Genetic testing - FSH Society

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