Structural variation in nebulin and its impact on phenotype and inheritance: establishing a dominant distal phenotype...

Structural variants (SVs) of the nebulin gene (NEB), including intragenic duplications, deletions, and copy number variation of the triplicate region, are an established cause of recessively inherited nemaline myopathies and related neuromuscular disorders. Large deletions have been shown to cause dominantly inherited distal myopathies. Here we provide an overview of 35 families with muscle disorders caused by such SVs in NEB. Using custom Comparative Genomic Hybridization arrays, exome sequencing, short-read genome sequencing, custom Droplet Digital PCR, or Sanger sequencing, we identified pathogenic SVs in 35 families with NEB-related myopathies. In 23 families, recessive intragenic deletions and duplications or pathogenic gains of the triplicate region segregating with the disease in compound heterozygous form, together with a small variant in trans, were identified. In two families the SV was, however, homozygous. Eight of these families have not been described previously. In 12 families with a distal myopathy phenotype (of which 10 are previously unpublished), eight unique, large deletions encompassing 52-97 exons in either heterozygous (n = 10) or mosaic (n = 2) state were identified. In the families where inheritance was recessive, no correlation could be made between the types of variants and the severity of the disease. In contrast, all patients with large dominant deletions in NEB had milder, predominantly distal muscle weakness. For the first time, we establish a clear and statistically significant association between large NEB deletions and a form of distal myopathy. In addition, we provide the hitherto largest overview of the spectrum of SVs in NEB.