title: Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies.
abstract: 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.
authors.affiliation: Paediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Klein
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lillis
authors.forename: Iulia
authors.initials: I
authors.lastname: Munteanu
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Scoto
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhou
authors.forename: Ros
authors.initials: R
authors.lastname: Quinlivan
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.forename: Adnan Y
authors.initials: AY
authors.lastname: Manzur
authors.forename: Helen
authors.initials: H
authors.lastname: Roper
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Jeannet
authors.forename: Wojtek
authors.initials: W
authors.lastname: Rakowicz
authors.forename: David Hilton
authors.initials: DH
authors.lastname: Jones
authors.forename: Uffe Birk
authors.initials: UB
authors.lastname: Jensen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wraige
authors.forename: Natalie
authors.initials: N
authors.lastname: Trump
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schara
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmuller
authors.forename: Anna
authors.initials: A
authors.lastname: Sarkozy
authors.forename: Helen
authors.initials: H
authors.lastname: Kingston
authors.forename: Fiona
authors.initials: F
authors.lastname: Norwood
authors.forename: Maxwell
authors.initials: M
authors.lastname: Damian
authors.forename: Janbernd
authors.initials: J
authors.lastname: Kirschner
authors.forename: Cheryl
authors.initials: C
authors.lastname: Longman
authors.forename: Mark
authors.initials: M
authors.lastname: Roberts
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
authors.forename: Imelda
authors.initials: I
authors.lastname: Hughes
authors.forename: Kate
authors.initials: K
authors.lastname: Bushby
authors.forename: Caroline
authors.initials: C
authors.lastname: Sewry
authors.forename: Stephanie
authors.initials: S
authors.lastname: Robb
authors.forename: Stephen
authors.initials: S
authors.lastname: Abbs
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics*; D010375:Pedigree; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel