Dominant or recessive mutations in the RYR1 gene causing central core myopathy in Brazilian patients

Leonardo Galleni Leão 1, Lucas Santos Souza 1, Letícia Nogueira 1, Rita de Cássia Mingroni Pavanello 1, Juliana Gurgel-Giannetti 2, Umbertina C Reed 3, Acary S.B. Oliveira 4, Thais Cuperman 4, Ana Cotta 5, Julia FPaim 5, Mayana Zatz 1, Mariz Vainzof 1

1 Human Genome and Stem Cell Research Center, University of São Paulo, São Paulo, Brazil; 2 Depart of Pediatrics, Medical School of Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; 3 Department of Neurology, Medical School of the University of Sao Paulo, São Paulo, Brazil; 4 Department of Neurology and Neurosurgery, Division of Neuromuscular Disorders, Federal University of São Paulo (Unifesp), São Paulo SP, Brazil; 5 Department of Pathology SARAH Network of Rehabilitation Hospitals, Belo Horizonte, MG, Brazil

Central Core Disease (CCD) is an inherited neuromuscular disorder characterized by the presence of cores in muscle biopsy. CCD is caused by mutations in the RYR1 gene. This gene encodes the ryanodine receptor 1, which is an intracellular calcium release channel from the sarcoplasmic reticulum to the cytosol in response to depolarization of the plasma membrane. Mutations in this gene are also associated with susceptibility to Malignant Hyperthermia (MHS).

In this study, we evaluated 20 families with clinical and histological characteristics of CCD to identify primary mutations in patients, for diagnosis and genetic counseling of the families.

We identified variants in the RYR1 gene in 19/20 families. The molecular pathogenicity was confirmed in 16 of them. Most of these variants (22/23) are missense and unique in the families. Two variants were recurrent in two different families. We identified six families with biallelic mutations, five compound heterozygotes with no consanguinity, and one homozygous, with consanguineous parents, resulting in 30% of cases with possible autosomal recessive inheritance. We identified seven novel variants, four of them classified as pathogenic. In one family, we identified two mutations in exon 102, segregating in cis, suggesting an additive effect of two mutations in the same allele.

This work highlights the importance of using Next-Generation Sequencing technology for the molecular diagnosis of genetic diseases when a very large gene is involved, associated to a broad distribution of the mutations along it. These data also influence the prevention through adequate genetic counseling for the families and cautions against malignant hyperthermia susceptibility. 

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