title: Segregation between SMCHD1 mutation, D4Z4 hypomethylation and Facio-Scapulo-Humeral Dystrophy: a case report.
abstract: BACKGROUND
  The main form of Facio-Scapulo-Humeral muscular Dystrophy is linked to copy number reduction of the 4q D4Z4 macrosatellite (FSHD1). In 5 % of cases, FSHD phenotype appears in the absence of D4Z4 reduction (FSHD2). In 70-80 % of these patients, variants of the SMCHD1 gene segregate with 4qA haplotypes and D4Z4 hypomethylation.
  
  
  METHODS
  We report a family presenting with neuromuscular symptoms reminiscent of FSHD but without D4Z4 copy reduction. We characterized the 4q35 region using molecular combing, searched for mutation in the SMCHD1 gene and determined D4Z4 methylation level by sodium bisulfite sequencing. We further investigated the impact of the SMCHD1 mutation at the protein level and on the NMD-dependent degradation of transcript. In muscle, we observe moderate but significant reduction in D4Z4 methylation, not correlated with DUX4-fl expression. Exome sequencing revealed a heterozygous insertion of 7 bp in exon 37 of the SMCHD1 gene producing a loss of frame with premature stop codon 4 amino acids after the insertion (c.4614-4615insTATAATA). Both wild-type and mutated transcripts are detected.
  
  
  CONCLUSIONS
  The truncated protein is absent and the full-length protein level is similar in patients and controls indicating that in this family, FSHD is not associated with SMCHD1 haploinsufficiency.
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, Marseille, France.
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Gaillard
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, Marseille, France.
authors.forename: Francesca
authors.initials: F
authors.lastname: Puppo
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, Marseille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Roche
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, Marseille, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Dion
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, Marseille, France.|APHM, Centre de Référence des Maladies Neuromusculaires et de la SLA, Hôpital de la Timone, Marseille, 13385, France.
authors.forename: Emmanuelle Salort
authors.initials: ES
authors.lastname: Campana
authors.affiliation: Center of Research in Myology/ Institut de Myologie UMR974 - UPMC Université Paris 6/ Inserm /FRE3617- CNRS, Groupement Hospitalier de la Pitié Salpétrière, Paris, Cedex 13, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Mariot
authors.affiliation: APHM, Laboratoire de Génétique Médicale, Hôpital de la Timone, Marseille, 13385, France.
authors.forename: Charlene
authors.initials: C
authors.lastname: Chaix
authors.affiliation: APHM, Laboratoire de Génétique Médicale, Hôpital de la Timone, Marseille, 13385, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vovan
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, Marseille, France.
authors.forename: Killian
authors.initials: K
authors.lastname: Mazaleyrat
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, Marseille, France.
authors.forename: Armand
authors.initials: A
authors.lastname: Tasmadjian
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, Marseille, France.|APHM, Laboratoire de Génétique Médicale, Hôpital de la Timone, Marseille, 13385, France.
authors.forename: Rafaelle
authors.initials: R
authors.lastname: Bernard
authors.affiliation: Center of Research in Myology/ Institut de Myologie UMR974 - UPMC Université Paris 6/ Inserm /FRE3617- CNRS, Groupement Hospitalier de la Pitié Salpétrière, Paris, Cedex 13, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Dumonceaux
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, Marseille, France.|APHM, Centre de Référence des Maladies Neuromusculaires et de la SLA, Hôpital de la Timone, Marseille, 13385, France.
authors.forename: Shahram
authors.initials: S
authors.lastname: Attarian
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, Marseille, France.|APHM, Laboratoire de Génétique Médicale, Hôpital de la Timone, Marseille, 13385, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, Marseille, France.|APHM, Laboratoire de Génétique Médicale, Hôpital de la Timone, Marseille, 13385, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, Marseille, France. frederique.magdinier@univ-amu.fr.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Magdinier
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, Marseille, France.|APHM, Laboratoire de Génétique Médicale, Hôpital de la Timone, Marseille, 13385, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Bartoli
mesh_terms: D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D020090:Chromosome Segregation; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D019175:DNA Methylation; D006801:Humans; D018895:Microsatellite Repeats; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics*; D009154:Mutation; D010375:Pedigree
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C578241:SMCHD1 protein, human
keywords: DNA combing; DNA methylation; DUX4; Facio-Scapulo-Humeral Dystrophy; Haploinsufficiency; SMCHD1