Silent polymorphisms in the RYR1 gene do not modify the phenotype of the p.4898 I>T pathogenic mutation in central core disease: a case reportReportar como inadecuado

Silent polymorphisms in the RYR1 gene do not modify the phenotype of the p.4898 I>T pathogenic mutation in central core disease: a case report - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

BMC Research Notes

, 7:487

First Online: 01 August 2014Received: 11 February 2014Accepted: 25 July 2014DOI: 10.1186-1756-0500-7-487

Cite this article as: Cuperman, T., Fernandes, S.A., Lourenço, N.C. et al. BMC Res Notes 2014 7: 487. doi:10.1186-1756-0500-7-487


BackgroundCentral core disease is a congenital myopathy, characterized by presence of central core-like areas in muscle fibers. Patients have mild or moderate weakness, hypotonia and motor developmental delay. The disease is caused by mutations in the human ryanodine receptor gene RYR1, which encodes a calcium-release channel. Since the RYR1 gene is huge, containing 106 exons, mutation screening has been limited to three ‘hot spots’, with particular attention to the C-terminal region. Recent next- generation sequencing methods are now identifying multiple numbers of variants in patients, in which interpretation and phenotype prevision is difficult.

Case presentationIn a Brazilian Caucasian family, clinical, histopathological and molecular analysis identified a new case of central core disease in a 48-year female. Sanger sequencing of the C-terminal region of the RYR1 gene identified two different missense mutations: c.14256 A > C polymorphism in exon 98 and c.14693 T > C in exon 102, which have already been described as pathogenic. Trans-position of the 2 mutations was confirmed because patient’s daughter, mother and sister carried only the exon 98’s mutation, a synonymous variant that was subsequently found in the frequency of 013–0,05 of alleles. Further next generation sequencing study of the whole RYR1 gene in the patient revealed the presence of additional 5 common silent polymorphisms in homozygosis and 8 polymorphisms in heterozygosis.

ConclusionsConsidering that patient’s relatives showed no pathologic phenotype, and the phenotype presented by the patient is within the range observed in other central core disease patients with the same mutation, it was concluded that the c.14256 A > C polymorphism alone is not responsible for disease, and the associated additional silent polymorphisms are not acting as modifiers of the primary pathogenic mutation in the affected patient. The case described above illustrates the present reality where new methods for wide genome screening are becoming more accessible and able to identify a great variety of mutations and polymorphisms of unknown function in patients and their families.

KeywordsCongenital myopathies Central core disease Ryanodin receptor 1 gene RYR1 Modifying effect Genotype-phenotype correlations AbbreviationsCCDCentral core disease

CKCreatine kinase


MHMalignant hyperthermia

NADHAdenine dinucleotide-tetrazolium reductase

NGSNext generation sequencing

RYR1Ryanodin receptor gene 1.

Electronic supplementary materialThe online version of this article doi:10.1186-1756-0500-7-487 contains supplementary material, which is available to authorized users.

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Autor: Thais Cuperman - Stephanie A Fernandes - Naila CV Lourenço - Lydia U Yamamoto - Helga CA Silva - Rita CM Pavanello - G


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