01P Structural variation in nebulin and its implications on phenotype and inheritance: establishing a dominant distal phenotype caused by large deletions

• Published in: Neuromuscular disorders : NMD 2024-10, Vol.43, p.104441, Article 104441.199
• Main Authors: Sagath, L., Kiiski, K., Naidu, K., Djordjevic, D., Yoon, G., Rogers, C., Scherer, K., Koparir, E., Kunstmann, E., Davis, M., Joshi, P., Zygmunt, A., Bönnemann, C., Biancalana, V., Echaniz-Laguna, A., Beggs, A., Henning, F., Wallgren-Pettersson, C., Pelin, K., Lehtokari, V.
• Format: Article
• Language: English
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.208

Structural variants of the nebulin gene (NEB), including duplications and deletions of up to 24 exons, and copy number variation of the triplicate region, are an established cause of recessive nemaline myopathies and related neuromuscular disorders. Large in-frame deletions have been shown to cause dominantly inherited distal myopathies. Here, we provide an overview of 32 families with muscle disorders caused by such intragenic structural variants in NEB. The sub-cohorts with recessively inherited phenotypes consist of 12 families with pathogenic gains of the triplicate region, and 11 families with ten unique intragenic deletions or duplications. In these 23 families, the structural variants cause disease through compound heterozygosity with small variants in trans, except in two families, in which the structural variant is homozygous. Eight families have not been previously described. The third sub-cohort consists of 12 families, of which 10 have not been previously described, with distal myopathy phenotypes caused by altogether eight unique deletions, encompassing 51 to 97 exons in size, in either heterozygous (n = 10) or mosaic (n = 2) state. The structural variants were identified using whole exome sequencing, whole genome sequencing, custom Droplet Digital PCR, or custom Comparative Genomic Hybridization arrays. Sanger sequencing was used to validate breakpoints in cases where applicable. 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 carrying a large dominant deletion in NEB were affected by milder, predominantly distal muscle weakness. Thus, for the first time, we establish a clear and statistically significant correlation (T-test, p < 0.0001) between large NEB deletions and distal myopathy. In addition, we provide the hitherto largest overview of the spectrum of structural variants in NEB.