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

摘要

Background: Central core disease is a congenital myopathy, characterized by presence of central core-like areas in\udmuscle fibers. Patients have mild or moderate weakness, hypotonia and motor developmental delay. The disease is\udcaused by mutations in the human ryanodine receptor gene (RYR1), which encodes a calcium-release channel.\udSince the RYR1 gene is huge, containing 106 exons, mutation screening has been limited to three ‘hot spots’, with\udparticular attention to the C-terminal region. Recent next- generation sequencing methods are now identifying\udmultiple numbers of variants in patients, in which interpretation and phenotype prevision is difficult.\udCase presentation: In a Brazilian Caucasian family, clinical, histopathological and molecular analysis identified a\udnew case of central core disease in a 48-year female. Sanger sequencing of the C-terminal region of the RYR1\udgene identified two different missense mutations: c.14256 A > C polymorphism in exon 98 and c.14693 T > C in\udexon 102, which have already been described as pathogenic. Trans-position of the 2 mutations was confirmed\udbecause patient’s daughter, mother and sister carried only the exon 98’s mutation, a synonymous variant that was\udsubsequently found in the frequency of 013–0,05 of alleles. Further next generation sequencing study of the whole\udRYR1 gene in the patient revealed the presence of additional 5 common silent polymorphisms in homozygosis and\ud8 polymorphisms in heterozygosis.\udConclusions: Considering that patient’s relatives showed no pathologic phenotype, and the phenotype presented\udby the patient is within the range observed in other central core disease patients with the same mutation, it was\udconcluded that the c.14256 A > C polymorphism alone is not responsible for disease, and the associated additional\udsilent polymorphisms are not acting as modifiers of the primary pathogenic mutation in the affected patient. The\udcase described above illustrates the present reality where new methods for wide genome screening are becoming\udmore accessible and able to identify a great variety of mutations and polymorphisms of unknown function in\udpatients and their families.