Background Subtelomeres are variable regions between telomeres and chromosomal-specific regions. One of the most studied pathologies linked to subtelomeric imbalance is facioscapulohumeral dystrophy (FSHD). In most cases, this disease involves shortening of an array of D4Z4 macrosatellite elements at the 4q35 locus. The disease also segregates with a specific A-type haplotype containing a degenerated polyadenylation signal distal to the last repeat followed by a repetitive array of β-satellite elements. This classification applies to most patients with FSHD. A subset of patients called FSHD2 escapes this definition and carries a mutation in the SMCHD1 gene. We also recently described patients carrying a complex rearrangement consisting of a cis-duplication of the distal 4q35 locus identified by molecular combing.
Methods Using this high-resolution technology, we further investigated the organisation of the 4q35 region linked to the disease and the 10q26 locus presenting with 98% of homology in controls and patients.
Results Our analyses reveal a broad variability in size of the different elements composing these loci highlighting the complexity of these subtelomeres and the difficulty for genomic assembly. Out of the 1029 DNA samples analysed in our centre in the last 7 years, we also identified 54 cases clinically diagnosed with FSHD carrying complex genotypes. This includes mosaic patients, patients with deletions of the proximal 4q region and 23 cases with an atypical chromosome 10 pattern, infrequently found in the control population and never reported before.
Conclusion Overall, this work underlines the complexity of these loci challenging the diagnosis and genetic counselling for this disease.
- facio scapulo humeral dystrophy
- molecular combing
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KN and NB contributed equally.
Contributors KN designed the study, supervised, conducted, analysed the combing experiments, and conducted a survey of the data presented. NB analysed the molecular combing data. SR performed and analysed whole-exome sequencing. JDR performed and analysed the pLAM assays. CV, CC and LG conducted and analysed Southern blots and molecular combing. AM, JAU, RB, CB, AD, BE, MF, VM, SS, VT, FZ, JMC, ESC and SA provided and clinically evaluated patients. RB analysed the MC data, conducted a survey and edited the manuscript. NL designed the study and edited the manuscript. FM analysed the data, wrote, edited and submitted the manuscript. KN and FM are responsible for the overall content as guarantor of the data presented.
Funding This study was funded by Association Française contre les Myopathies (AFM grantsNMDecrypt and TRIM-RD program) and Agence Nationale de la Recherche (ANR,FSHDecipher, ANR-13-BSV1-0001).
Competing interests A patent application (No. EP08165310.7) on molecular combing for the diagnosis of FSHD1 and exploration of D4Z4 has been registered by Genomic Vision, University of the Mediterranean, and Public Assistance of the Hospitals of Marseille. NL is a co-inventor of the patent.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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