Résumé :
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The genetic modifications associated with facioscapulohumeral dystrophy (FSHD), one of the most common hereditary muscular disorders are complex, including mainly the contraction of a D4Z4 repeat array at the 4q35 subtelomeric region together with a distal cis-polymorphism termed qA. Several factors such as non-pathogenic variants of 4q and homologous array on chromosome 10q complicate the diagnosis, as well as non-standard D4Z4 arrays in some individuals. We previously proposed the molecular combing (MC) technology as an alternative, new, and valuable tool for providing an accurate diagnosis of FSHD, compared to the current approaches. Based on the direct visualisation of allelic combinations associated with FSHD, MC was indeed validated in a large cohort of cases and allowed the precise discrimination of all 4qter and 10qter D4Z4 repeat arrays, revealing their size, their precise location, and their segregation within the genomic environment. Detection of standard deletions as well as rare 10qB haplotypes and somatic mosaics were facilitated with MC. We report here an update of the FSHD-MC diagnostic strategy with new improvements of the test design and diagnostic process. We also report atypical findings at the FSHD locus such as large deletions extending into the proximal P13E-11 probe region, non standard D4Z4 arrays at chromosomes 4 and 10, re-arrangements such as duplications and translocations of D4Z4 arrays. These new findings further confirm the relevance and reliability of this technique for the FSHD diagnosis and also the major input of the MC technology to explore the detailed genomic structure of this locus in a research background.From a practical point of view, the global turnaround time for MC is one week for a complete analysis. Automation of the technology is in progress and FSHD-MC testing is becoming the reference diagnostic method to replace Southern analysis in our laboratory.
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