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J Med Genet. 2019 Sep;56(9):590-601. doi: 10.1136/jmedgenet-2018-105949. Epub 2019 Apr 22.

Deciphering the complexity of the 4q and 10q subtelomeres by molecular combing in healthy individuals and patients with facioscapulohumeral dystrophy.

Author information

Medical Genetics, Assistance Publique Hopitaux de Marseille, Marseille, France.
Aix Marseille Univ, INSERM, MMG, Marseille Medical Genetics U1251, Marseille, France.
Genetique, Institut Jerome Lejeune, Paris, France.
Pôle Soins de suite et réadaptation handicaps lourds et maladies rares neurologiques, Hôpital Marin, Assistance publique des hopitaux de Paris, Hendaye, France.
Hopital Pierre Zobda-Quitman, Fort-de-France, France.
Service de Neurologie infantile, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
Centre de Référence de Maladies Neuromusculaires Garches-Necker-Mondor-Hendaye (GNMH), Réseau National Français de la Filière Neuromusculaire (FILNEMUS), Paris, France.
Génétique Médicale, CHU-Nantes, Nantes, France.
Assistance Publique - Hopitaux de Paris, Paris, Île-de-France, France.
Service de Génétique Médicale, Centre De Référence Anomalies du Développement, CHU de Rennes, Rennes, France.
Centre référent maladies neuromusculaires rares, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Bron, France.
Peripheral Nervous System, Muscle and ALS Department, Université Côte d'Azur, Nice, France.
Institute for Research on Cancer and Aging of Nice, Université Côte d'Azur, Faculty of Medicine, Nice, France.
Centre de Référence des Maladies Neuromusculaires, service de Médecine Physique et de Réadaptation, Centre hospitalier régionale de Lille, Lille, France.
Centre de Référence des Maladies Neuromusculaires, CHU Morvan, Brest, France.
Service de Neuropédiatrie, CHRU de Lille, Lille, France.
Centre de reference des maladies neuromusculaires, Assistance Publique Hopitaux de Marseille, Marseille, France.
Aix Marseille Univ, INSERM, MMG, Marseille Medical Genetics U1251, Marseille, France
Contributed equally



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.


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.


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.


Overall, this work underlines the complexity of these loci challenging the diagnosis and genetic counselling for this disease.


facio scapulo humeral dystrophy; molecular combing; smchd1; subtelomeres

Conflict of interest statement

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.

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