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SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain
  1. Richard J L F Lemmers1,
  2. Nienke van der Stoep2,
  3. Patrick J van der Vliet1,
  4. Steven A Moore3,
  5. David San Leon Granado1,
  6. Katherine Johnson4,
  7. Ana Topf4,
  8. Volker Straub4,
  9. Teresinha Evangelista5,
  10. Tahseen Mozaffar6,
  11. Virginia Kimonis7,
  12. Natalie D Shaw8,
  13. Rita Selvatici9,
  14. Alessandra Ferlini10,
  15. Nicol Voermans11,
  16. Baziel van Engelen11,
  17. Sabrina Sacconi12,
  18. Rabi Tawil13,
  19. Meindert Lamers14,
  20. Silvère M van der Maarel1
  1. 1 Human Genetics, Leids Universitair Medisch Centrum, Leiden, The Netherlands
  2. 2 Department of Clinical Genetics, Laboratory for Diagnostic Genome Analysis, Leids Universitair Medisch Centrum, Leiden, The Netherlands
  3. 3 Department of Pathology, University of Iowa, Iowa City, Iowa, USA
  4. 4 John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle upon Tyne, UK
  5. 5 Unité de Morphologie Neuromusculaire, Institut de Myologie, Paris, France
  6. 6 Department of Neurology, University of California Irvine, Irvine, California, USA
  7. 7 Department of Pediatrics, University of California, Irvine, Irvine, California, USA
  8. 8 National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
  9. 9 Department of Medical Sciences; Medical Genetics Unit, University of Ferrara, Ferrara, Italy
  10. 10 Dipartimento di Medicina Sperimentale e Diagnostica, Università di Ferrara, Ferrara, Italy
  11. 11 Department of Neurology, Radboudumc, Nijmegen, Gelderland, The Netherlands
  12. 12 Centre de Référence Maladies Neuromusculaires, Hôpital Archet, Nice, France
  13. 13 Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA
  14. 14 Department of Cell and Chemical Biology, Leiden Universitair Medisch Centrum, Leiden, The Netherlands
  1. Correspondence to Dr Richard J L F Lemmers, Human Genetics, Leids Universitair Medisch Centrum, Leiden 2333 ZA, The Netherlands; r.j.l.f.lemmers{at}


Background Variants in the Structural Maintenance of Chromosomes flexible Hinge Domain-containing protein 1 (SMCHD1) can cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) and the unrelated Bosma arhinia microphthalmia syndrome (BAMS). In FSHD2, pathogenic variants are found anywhere in SMCHD1 while in BAMS, pathogenic variants are restricted to the extended ATPase domain. Irrespective of the phenotypic outcome, both FSHD2-associated and BAMS-associated SMCHD1 variants result in quantifiable local DNA hypomethylation. We compared FSHD2, BAMS and non-pathogenic SMCHD1 variants to derive genotype–phenotype relationships.

Methods Examination of SMCHD1 variants and methylation of the SMCHD1-sensitive FSHD locus DUX4 in 187 FSHD2 families, 41 patients with BAMS and in control individuals. Analysis of variants in a three-dimensional model of the ATPase domain of SMCHD1.

Results DUX4 methylation analysis is essential to establish pathogenicity of SMCHD1 variants. Although the FSHD2 mutation spectrum includes all types of variants covering the entire SMCHD1 locus, missense variants are significantly enriched in the extended ATPase domain. Identification of recurrent variants suggests disease-specific residues for FSHD2 and in BAMS, consistent with a largely disease-specific localisation of variants in SMCHD1.

Conclusions The localisation of missense variants within the ATPase domain of SMCHD1 may contribute to the differences in phenotypic outcome.

  • FSHD
  • BAMS
  • D4Z4
  • SMCHD1
  • DUX4
  • mutation spectrum
  • ATPase domain

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  • Correction notice The article has been further corrected since the Online First version was amended. The affiliation of author NDS and details on her funding have been, respectively, corrected and added.

  • Contributors RJLFL and SMvdM contributed to the study design and conception of study. RJLFL, NvdS, PJvdV, SAM, KJ, AT, VS, TE, TM, VK, NDS, RS, AF, NV, BvE, SS and RT contributed to the data collection and assembly. RJLFL, NvdS, PJvdV, SAM, DSLG, ML and SMM contributed to the data analysis and interpretation. RJLFL, ML and SMM contributed to the writing of manuscript. RJLFL, NvdS, PJvdV, SAM, NV, ML and SMvdM critical reviewed and revised the manuscript. RJLFL submitted the manuscript.

  • Funding This study was funded by Iowa Wellstone Muscular Dystrophy Cooperative Research Center, U54 (NS053672) and National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR045203). For this work NDS was supported, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (1ZIAES103327-02).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Medical Ethical Committee from the Leiden University Medical Center

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

  • Data sharing statement Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information.