Mutation Update: The Spectra of Nebulin Variants and Associated Myopathies |
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| Authors: | Vilma‐Lotta Lehtokari Kirsi Kiiski Sarah A Sandaradura Jocelyn Laporte Pauliina Repo Jennifer A Frey Kati Donner Minttu Marttila Carol Saunders Peter G Barth Johan T den Dunnen Alan H Beggs Nigel F Clarke Kathryn N North Nigel G Laing Norma B Romero Thomas L Winder Katarina Pelin Carina Wallgren‐Pettersson |
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| Institution: | 1. The Folkh?lsan Institute of Genetics and the Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland;2. INMR, The Children's Hospital at Westmead and Sydney Medical School, University of Sydney, Sydney, Australia;3. Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, Australia;4. Department of Translational Medicine, IGBMC, Inserm U964, CNRS UMR7104, Collège de France, Strasbourg University, Illkirch, France;5. Prevention Genetics Marshfield, Marshfield, Wisconsin;6. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland;7. Center for Pediatric Genomic Medicine Children's Mercy Hospitals and Clinics, Kansas City, Missouri;8. Department of Pediatric Neurology, Emma Children's Hospital/AMC, University of Amsterdam, Amsterdam, The Netherlands;9. Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands;10. Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;11. Murdoch Childrens Research, Melbourne, Australia;12. Centre for Medical Research University of Western Australia and Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Perth, Australia;13. Myology Institute, UPMC Paris‐6, INSERM UMR 974, GHU La Pitié‐Salpêtrière, Paris, France;14. Department of Biosciences, Division of Genetics, University of Helsinki, Helsinki, Finland |
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| Abstract: | A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core‐rod myopathy and in distal myopathies. In this update, we present the disease‐causing variants in NEB in 159 families, 143 families with NM, and 16 families with NM‐related myopathies. Eighty‐eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server ( http://evs.gs.washington.edu/EVS/ ), identifying that pathogenic variants are a minor fraction of all coding variants (～7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype–phenotype correlations in NEB‐associated disease. |
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| Keywords: | nebulin NEB nemaline (rod) myopathy actin– myosin sarcomere |
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