contributed equally to this work.
Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies†
Article first published online: 4 APR 2012
© 2012 Wiley Periodicals, Inc.
Special Issue: Focus on CNV Detection with Diagnostic Arrays
Volume 33, Issue 6, pages 981–988, June 2012
How to Cite
Klein, A., Lillis, S., Munteanu, I., Scoto, M., Zhou, H., Quinlivan, R., Straub, V., Manzur, A. Y., Roper, H., Jeannet, P.-Y., Rakowicz, W., Jones, D. H., Jensen, U. B., Wraige, E., Trump, N., Schara, U., Lochmuller, H., Sarkozy, A., Kingston, H., Norwood, F., Damian, M., Kirschner, J., Longman, C., Roberts, M., Auer-Grumbach, M., Hughes, I., Bushby, K., Sewry, C., Robb, S., Abbs, S., Jungbluth, H. and Muntoni, F. (2012), Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies. Hum. Mutat., 33: 981–988. doi: 10.1002/humu.22056
Communicated by Jürgen Horst
- Issue published online: 7 MAY 2012
- Article first published online: 4 APR 2012
- Accepted manuscript online: 21 FEB 2012 12:17PM EST
- Manuscript Accepted: 7 FEB 2012
- Manuscript Received: 18 NOV 2011
- Guy's & St Thomas' Charity (to H.J.; #G070404); National Commissioning Group (to Dubowitz Neuromuscular Centre for Congenital Muscular Dystrophies and Congenital Myopathies); Muscular Dystrophy Campaign (to Dubowitz Neuromuscular Centre); Medical Research Council MRC (to the Neuromuscular Biobank at UCL). FM was supported by Great Ormond Street Hospital Children's Charity and the Muscular Dystrophy Association MDA (to F.M. and I.M.); the Austrian Science Fond (to M.AG; FWF, P23223-B19)
Vol. 33, Issue 8, 1310, Article first published online: 13 JUL 2012
- congenital myopathy;
- core myopathies
Ryanodine receptor 1 (RYR1) mutations are a common cause of congenital myopathies associated with both dominant and recessive inheritance. Histopathological findings frequently feature central cores or multi-minicores, more rarely, type 1 predominance/uniformity, fiber-type disproportion, increased internal nucleation, and fatty and connective tissue. We describe 71 families, 35 associated with dominant RYR1 mutations and 36 with recessive inheritance. Five of the dominant mutations and 35 of the 55 recessive mutations have not been previously reported. Dominant mutations, typically missense, were frequently located in recognized mutational hotspot regions, while recessive mutations were distributed throughout the entire coding sequence. Recessive mutations included nonsense and splice mutations expected to result in reduced RyR1 protein. There was wide clinical variability. As a group, dominant mutations were associated with milder phenotypes; patients with recessive inheritance had earlier onset, more weakness, and functional limitations. Extraocular and bulbar muscle involvement was almost exclusively observed in the recessive group. In conclusion, our study reports a large number of novel RYR1 mutations and indicates that recessive variants are at least as frequent as the dominant ones. Assigning pathogenicity to novel mutations is often difficult, and interpretation of genetic results in the context of clinical, histological, and muscle magnetic resonance imaging findings is essential. Hum Mutat 33:981–988, 2012. © 2012 Wiley Periodicals, Inc.