title: Low penetrance in facioscapulohumeral muscular dystrophy type 1 with large pathological D4Z4 alleles: a cross-sectional multicenter study.
abstract: BACKGROUND
  Facioscapulohumeral muscular dystrophy type 1(FSHD1) is an autosomal dominant disorder associated with the contraction of D4Z4 less than 11 repeat units (RUs) on chromosome 4q35. Penetrance in the range of the largest alleles is poorly known. Our objective was to study the penetrance of FSHD1 in patients carrying alleles ranging between 6 to10 RUs and to evaluate the influence of sex, age, and several environmental factors on clinical expression of the disease.
  
  
  METHODS
  A cross-sectional multicenter study was conducted in six French and one Swiss neuromuscular centers. 65 FSHD1 affected patients carrying a 4qA allele of 6-10 RUs were identified as index cases (IC) and their 119 at-risk relatives were included. The age of onset was recorded for IC only. Medical history, neurological examination and manual muscle testing were performed for each subject. Genetic testing determined the allele size (number of RUs) and the 4qA/4qB allelic variant. The clinical status of relatives was established blindly to their genetic testing results. The main outcome was the penetrance defined as the ratio between the number of clinically affected carriers and the total number of carriers.
  
  
  RESULTS
  Among the relatives, 59 carried the D4Z4 contraction. At the clinical level, 34 relatives carriers were clinically affected and 25 unaffected. Therefore, the calculated penetrance was 57% in the range of 6-10 RUs. Penetrance was estimated at 62% in the range of 6-8 RUs, and at 47% in the range of 9-10 RUs. Moreover, penetrance was lower in women than men. There was no effect of drugs, anesthesia, surgery or traumatisms on the penetrance.
  
  
  CONCLUSIONS
  Penetrance of FSHD1 is low for largest alleles in the range of 9-10 RUs, and lower in women than men. This is of crucial importance for genetic counseling and clinical management of patients and families.
authors.affiliation: AP-HM, Reference Center of Neuromuscular Disorders and ALS, Timone University Hospital, Aix-Marseille University, 264 rue Saint-Pierre, Marseille, Cedex 05, 13385, France. emmanuelle.salort-campana@ap-hm.fr.|Aix Marseille Université - Inserm UMR_S 910 Medical Genetics and Functional Genomics, Marseille, France. emmanuelle.salort-campana@ap-hm.fr.|AP-HM, Department of Medical Genetics, Timone University Hospital, Marseille, France. emmanuelle.salort-campana@ap-hm.fr.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Salort-Campana
authors.affiliation: Aix Marseille Université - Inserm UMR_S 910 Medical Genetics and Functional Genomics, Marseille, France. karine.nguyen@ap-hm.fr.|AP-HM, Department of Medical Genetics, Timone University Hospital, Marseille, France. karine.nguyen@ap-hm.fr.
authors.forename: Karine
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Aix Marseille Université - Inserm UMR_S 910 Medical Genetics and Functional Genomics, Marseille, France. rafaelle.bernard@ap-hm.fr.|AP-HM, Department of Medical Genetics, Timone University Hospital, Marseille, France. rafaelle.bernard@ap-hm.fr.
authors.forename: Rafaelle
authors.initials: R
authors.lastname: Bernard
authors.affiliation: CIC-UPCET, Timone University Hospital, AP-HM, UMR CNRS Aix-Marseille University 6193, Marseille, France. elisabeth.jouve@ap-hm.fr.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Jouve
authors.affiliation: Reference Center of Neuromuscular Disorders, CHU of Bordeaux, Pessac, France. guilhem.sole@chu-bordeaux.fr.
authors.forename: Guilhem
authors.initials: G
authors.lastname: Solé
authors.affiliation: Centre de Référence des Maladies Neuromusculaires Nantes-Angers, Service de Neurologie, CHU d'Angers, Angers, France. alpakleza@chu-angers.fr.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Nadaj-Pakleza
authors.affiliation: Nerve-Muscle Unit, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), Lausanne, Switzerland. julien.niederhauser@ghol.ch.
authors.forename: Julien
authors.initials: J
authors.lastname: Niederhauser
authors.affiliation: CIC-UPCET, Timone University Hospital, AP-HM, UMR CNRS Aix-Marseille University 6193, Marseille, France. estelle.charles@ap-hm.fr.
authors.forename: Estelle
authors.initials: E
authors.lastname: Charles
authors.affiliation: Croix-Rousse Hospital, Lyon, France. elisabeth.ollagnon@chu-lyon.fr.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ollagnon
authors.affiliation: Electroneuromyography and Neuromuscular Department, GHE Neurologic hospital, Lyon, Bron Cedex, 69677, France. francoise.bouhour@chu-lyon.fr.
authors.forename: Françoise
authors.initials: F
authors.lastname: Bouhour
authors.affiliation: Neuromuscular Disease Specialized Center, Nice University Hospital, Nice, France. SACCONI.S@chu-nice.fr.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sacconi
authors.affiliation: Reference Center of Neuromuscular Disorders, Neurology Department, Hautepierre Hospital, Strasbourg, France. andoni.echaniz-laguna@chru-strasbourg.fr.
authors.forename: Andoni
authors.initials: A
authors.lastname: Echaniz-Laguna
authors.affiliation: Neuromuscular Disease Specialized Center, Nice University Hospital, Nice, France. desnuelle.c@chu-nice.fr.
authors.forename: Claude
authors.initials: C
authors.lastname: Desnuelle
authors.affiliation: Reference Center of Neuromuscular Disorders, Neurology Department, Hautepierre Hospital, Strasbourg, France. christine.tranchant@chru-strasbourg.fr.
authors.forename: Christine
authors.initials: C
authors.lastname: Tranchant
authors.affiliation: Electroneuromyography and Neuromuscular Department, GHE Neurologic hospital, Lyon, Bron Cedex, 69677, France. christophe.vial@chu-lyon.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Vial
authors.affiliation: Aix Marseille Université - Inserm UMR_S 910 Medical Genetics and Functional Genomics, Marseille, France. frederique.magdinier@univ-amu.fr.
authors.forename: Frederique
authors.initials: F
authors.lastname: Magdinier
authors.affiliation: Aix Marseille Université - Inserm UMR_S 910 Medical Genetics and Functional Genomics, Marseille, France. marc.bartoli@univ-amu.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Bartoli
authors.affiliation: Reference Center of Neuromuscular Disorders, CHU of Toulouse, Toulouse, France. arne-bes.mc@chu-toulouse.fr.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Arne-Bes
authors.affiliation: Reference Center of Neuromuscular Disorders, CHU of Bordeaux, Pessac, France. xavier.ferrer@chu-bordeaux.fr.
authors.forename: Xavier
authors.initials: X
authors.lastname: Ferrer
authors.affiliation: Nerve-Muscle Unit, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), Lausanne, Switzerland. thierry.kuntzer@chuv.ch.
authors.forename: Thierry
authors.initials: T
authors.lastname: Kuntzer
authors.affiliation: Aix Marseille Université - Inserm UMR_S 910 Medical Genetics and Functional Genomics, Marseille, France. nicolas.levy@univ-amu.fr.|AP-HM, Department of Medical Genetics, Timone University Hospital, Marseille, France. nicolas.levy@univ-amu.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Levy
authors.affiliation: AP-HM, Reference Center of Neuromuscular Disorders and ALS, Timone University Hospital, Aix-Marseille University, 264 rue Saint-Pierre, Marseille, Cedex 05, 13385, France. jean.pouget@ap-hm.fr.|Aix Marseille Université - Inserm UMR_S 910 Medical Genetics and Functional Genomics, Marseille, France. jean.pouget@ap-hm.fr.
authors.forename: Jean
authors.initials: J
authors.lastname: Pouget
authors.affiliation: AP-HM, Reference Center of Neuromuscular Disorders and ALS, Timone University Hospital, Aix-Marseille University, 264 rue Saint-Pierre, Marseille, Cedex 05, 13385, France. shahram.attarian@ap-hm.fr.
authors.forename: Shahram
authors.initials: S
authors.lastname: Attarian
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D003430:Cross-Sectional Studies; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019683:Penetrance; D016601:RNA-Binding Proteins; D055815:Young Adult
chemical_list: C101270:FRG1 protein, human; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins