1The Folkhälsan Institute of Genetics and the Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland2INMR, The Children's Hospital at Westmead and Sydney Medical School, University of Sydney, Sydney, Australia3Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, Australia4Department of Translational Medicine, IGBMC, Inserm U964, CNRS UMR7104, Collège de France, Strasbourg University, Illkirch, France5Prevention Genetics Marshfield, Marshfield, Wisconsin,6Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland7Center for Pediatric Genomic Medicine Children's Mercy Hospitals and Clinics, Kansas City, Missouri,8Department of Pediatric Neurology, Emma Children's Hospital/AMC, University of Amsterdam, Amsterdam, The Netherlands9Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands10Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts,11Murdoch Childrens Research, Melbourne, Australia12Centre for Medical Research University of Western Australia and Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Perth, Australia13Myology Institute, UPMC Paris-6, INSERM UMR 974, GHU La Pitié-Salpêtrière, Paris, France14Department of Biosciences, Division of Genetics, University of Helsinki, Helsinki, Finland
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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 inNEBare the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenicNEBvariants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants inNEBin 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 We summarize 86 previously published and 126 unpublished variants identified inNEB. Furthermore, we have analyzed theNEBvariants 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 inNEB-associated disease.Variants in the nebulin gene are the most common cause of autosomal recessive nemaline myopathy, but the clinical and histological spectrum is a continuum ranging from severe to mild forms of congenital myopathies. The spectrum of pathogenic variants range from point mutations to large deletions and duplications covering large parts of the gene. Amino acid changes are very common in nebulin, but only few of them are disease-causing. Detailed genotype-phenotype correlations are difficult to discern.