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Extending the clinical and mutational spectrum of TRIM32-related myopathies in a non-Hutterite population
  1. Katherine Johnson1,
  2. Willem De Ridder2,3,4,
  3. Ana Töpf1,
  4. Marta Bertoli1,
  5. Lauren Phillips1,
  6. Peter De Jonghe2,3,4,
  7. Jonathan Baets2,3,4,
  8. Tine Deconinck2,3,
  9. Vidosava Rakocevic Stojanovic5,
  10. Stojan Perić5,
  11. Hacer Durmus6,
  12. Shirin Jamal-Omidi7,
  13. Shahriar Nafissi7,
  14. Tiziana Mongini8,
  15. Anna Łusakowska9,
  16. Mark Busby10,
  17. James Miller11,
  18. Fiona Norwood12,
  19. Judith Hudson13,
  20. Rita Barresi1,14,
  21. Monkol Lek15,16,
  22. Daniel G MacArthur15,16,
  23. Volker Straub1
  1. 1 John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
  2. 2 Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium
  3. 3 Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
  4. 4 Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium
  5. 5 Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia
  6. 6 Department of Neurology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
  7. 7 Iranian Center of Neurological Research, Tehran University of Medical Sciences, Tehran, Iran
  8. 8 Department of Neurosciences ‘Rita Levi Montalcini’, University of Turin, Turin, Italy
  9. 9 Department of Neurology, Medical University of Warsaw, Warsaw, Poland
  10. 10 Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK
  11. 11 The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
  12. 12 King’s College Hospital, London, UK
  13. 13 Northern Molecular Genetics Service, Biomedicine East Wing, Newcastle upon Tyne, UK
  14. 14 Muscle Immunoanalysis Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
  15. 15 Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
  16. 16 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
  1. Correspondence to Professor Volker Straub, The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle upon Tyne, NE1 3BZ, UK; volker.straub{at}

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TRIM32-related myopathies represent a phenotypic spectrum of a rare autosomal recessive muscle disorder. The disease is described as a mild and progressive myopathy without characteristic clinical features. Originally classified as limb-girdle muscular dystrophy (LGMD) 2H (OMIM #254110), the disorder was first identified in the Hutterite population and the homozygous TRIM32 founder mutation, p.Asp487Asn, was identified as the cause of this disease.1 Only seven patients with definite non-Hutterite TRIM32-related myopathy have been reported in the literature. Apart from two missense mutations residing in the NHL repeats of TRIM32, only deletions, frameshift and nonsense mutations have been reported.2 Having applied next generation sequencing technologies to over 1000 patients with suspected genetic muscle disorders, we present nine patients with TRIM32-related myopathies and three patients with a homozygous TRIM32 variant of unknown significance (VUS).

Subjects and methods

DNA samples from 1000 patients with unexplained limb-girdle muscle weakness and/or elevated serum creatine kinase (CK) levels were gathered through the MYO-SEQ project. Samples were processed and whole exome sequencing (WES) performed as described previously.3 Additional patients with TRIM32-related myopathy were diagnosed by the Northern Molecular Genetics Service (NMGS) diagnostic laboratory through panel sequencing of 32 LGMD genes. Variants were classified according to ACMG guidelines.4 MRI imaging was performed for eight patients on a 1.5T MRI platform. Muscle biopsies for all patients were analysed following standard histological techniques.


Genetic findings

Of the 1000 MYO-SEQ patients, we identified 36 with rare coding variants in TRIM32 (minor allele frequency <1%; numbered 1–36 in online supplementary table 1). Twenty-six patients had single heterozygous variants; these were discarded from our analysis as the variants were unlikely to be pathogenic in this autosomal recessive disease. Two further patients were excluded from our analysis: patient 18 was heterozygous for a pathogenic DES mutation and patient 10 was homozygous for a pathogenic CAPN3 …

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