title: 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.
abstract: BACKGROUND
  Central 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.
  
  
  METHODS
  In 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.
  
  
  CONCLUSIONS
  Considering 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.
authors.forename: Thais
authors.initials: T
authors.lastname: Cuperman
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Fernandes
authors.forename: Naila C V
authors.initials: NC
authors.lastname: Lourenço
authors.forename: Lydia U
authors.initials: LU
authors.lastname: Yamamoto
authors.forename: Helga C A
authors.initials: HC
authors.lastname: Silva
authors.forename: Rita C M
authors.initials: RC
authors.lastname: Pavanello
authors.forename: Guilherme L
authors.initials: GL
authors.lastname: Yamamoto
authors.forename: Mayana
authors.initials: M
authors.lastname: Zatz
authors.forename: Acary S B
authors.initials: AS
authors.lastname: Oliveira
authors.affiliation: Laboratory of Muscle Proteins and Comparative Histopathology, Human Genome Research Center, Biosciences Institute, University of São Paulo, R, do Matão, 106 - Cidade Universitária, São Paulo, SP CEP 05508-900, Brazil. mvainzof@usp.br.
authors.forename: Mariz
authors.initials: M
authors.lastname: Vainzof
mesh_terms: D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D020512:Myopathy, Central Core / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel
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