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FXR1-related congenital myopathy: expansion of the clinical and genetic spectrum
  1. Magdalena Mroczek1,2,
  2. Cheryl Longman3,
  3. Maria Elena Farrugia4,
  4. Solange Kapetanovic Garcia5,
  5. Didem Ardicli6,7,
  6. Haluk Topaloglu6,8,
  7. Aurelio Hernández-Laín9,
  8. Diclehan Orhan10,
  9. Mehmet Alikasifoglu11,
  10. Jennifer Duff2,
  11. Sabine Specht2,
  12. Kristen Nowak12,13,
  13. Gianina Ravenscroft13,
  14. Katherine Chao14,
  15. Zaheer Valivullah14,
  16. Sandra Donkervoort15,
  17. Dimah Saade15,
  18. Carsten Bönnemann15,
  19. Volker Straub2,
  20. Grace Yoon16,17
  1. 1 Department of Neurology and Neurophysiology, Balgrist University Hospital, Zurich, Switzerland
  2. 2 John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
  3. 3 West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow, UK
  4. 4 Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK
  5. 5 Unidad de ELA y Neuromuscular, Hospital Universitario de Basurto, Bilbao, Spain
  6. 6 Department of Pediatric Neurology, Hacettepe University Children's Hospital, Ankara, Turkey
  7. 7 Department of Pediatric Neurology, Ministry of Health, Ankara City Hospital, Ankara, Turkey
  8. 8 Department of Pediatrics, Yeditepe University, İstanbul, Turkey
  9. 9 Department of Pathology (Neuropathology), Hospital Universitario 12 de Octubre Research Institute (imas12), Madrid, Spain
  10. 10 Department of Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey
  11. 11 Department of Medical Genetics, Hacettepe University Children’s Hospital, Ankara, Turkey
  12. 12 School of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Western Australia, Nedlands, Western Australia, Australia
  13. 13 Centre of Medical Research, The University of Western Australia and the Harry Perkins Institute for Medical Research, Perth, Western Australia, Australia
  14. 14 Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
  15. 15 Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
  16. 16 Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
  17. 17 Divison of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr Grace Yoon, The Hospital for Sick Children Department of Paediatrics, Toronto, ON M5G 1X8, Canada; grace.yoon{at}; Professor Volker Straub, John Walton Muscular Dystrophy Research Centre, Institute of Translational and Clinical Research, Newcastle University, Newcastle, UK; volker.straub{at}


Background Biallelic pathogenic variants in FXR1 have recently been associated with two congenital myopathy phenotypes: a severe form associated with hypotonia, long bone fractures, respiratory insufficiency and infantile death, and a milder form characterised by proximal muscle weakness with survival into adulthood.

Objective We report eight patients from four unrelated families with biallelic pathogenic variants in exon 15 of FXR1.

Methods Whole exome sequencing was used to detect variants in FXR1.

Results Common clinical features were noted for all patients, which included proximal myopathy, normal serum creatine kinase levels and diffuse muscle atrophy with relative preservation of the quadriceps femoris muscle on muscle imaging. Additionally, some patients with FXR1-related myopathy had respiratory involvement and required bilevel positive airway pressure support. Muscle biopsy showed multi-minicores and type I fibre predominance with internalised nuclei.

Conclusion FXR1-related congenital myopathy is an emerging entity that is clinically recognisable. Phenotypic variability associated with variants in FXR1 can result from differences in variant location and type and is also observed between patients homozygous for the same variant, rendering specific genotype–phenotype correlations difficult. Our work broadens the phenotypic spectrum of FXR1-related congenital myopathy.

  • Neuromuscular Diseases

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  • VS and GY are joint senior authors.

  • Twitter @Gianina_Natoli

  • Contributors MM, CL, MEF, SKG, DA, HT, SD, DS, CB, VS and GY recruited and phenotyped the patients. MA, JD, SS, KN, GR, KC and ZV conducted molecular analyses and bioinformatics analysis of whole exome sequencing data. AH-L and DO conducted neuropathological studies. MM, VS and GY designed the study, and wrote the manuscript. VS and GY provided overall study supervision. All authors critically reviewed the manuscript.

  • Funding MYO-SEQ was funded by Sanofi Genzyme, Ultragenyx, LGMD2I Research Fund, Samantha J. Brazzo Foundation, LGMD2D Foundation and Kurt+Peter Foundation, Muscular Dystrophy UK, and Coalition to Cure Calpain 3. Analysis was provided by the Broad Institute of MIT and Harvard Centre for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900, and in part by National Human Genome Research Institute grant R01 HG009141. GR is funded by the NHMRC (APP1122952 and APP2002640). The work in C.G. Bönnemann’s laboratory is supported by intramural funds from the NIH National Institute of Neurological Disorders and Stroke.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.