Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene associated myopathies

Whole exome sequencing of a patient with suspected mitochondrial myopathy reveals novel compound heterozygous variants in RYR1

“…A second pathogenic deletion (Chr19(GRCh37): g.38969105_38969120del, NM_000540.2: c.4485_4500del, NP_000531.2: p.Tyr1495X) in RYR1 leads to a premature stop in exon 31 (SPIa/RYanodine Receptor SPRY domain) and was detected in the patient's father (Table 1). A patient with a c.4485G>A missense variant that results in an identical premature stop codon (p.Tyr1495X) in RYR1 has been previously described in Klein et al in an individual who presented >10 years of age with proximal weakness, scoliosis, and muscle biopsy that revealed type 1 predominance in both cores and minicores (Klein et al 2012). This individual also had two other missense variants of uncertain significance (VUS) in RYR1 including c.1453A>G; p.Met485Val and c.325C>T; p.Arg109Trp.…”

“…RYR1 is required for normal development of muscle fibers, skin, and heart during embryogenesis and pathogenic variation is thought to result in altered properties of RYR1 and changes in calcium homeostasis that can lead to a number of pathological states. RYR1 variants associated with susceptibility to malignant hyperthermia and central core disease are primarily dominant missense variants, and very few small deletions or duplications have been described (Klein et al 2012). These variants produce hypersensitive channels (prone to activation by muscle fiber depolarization) as in malignant hyperthermia or leaky (Ca 2+ dysregulation and depletion of Ca 2+ from the sarcoplasmic reticulum) RYR1 channels as in classic central core disease (Hern andez-Ochoa et al 2015).…”

“…These variants produce hypersensitive channels (prone to activation by muscle fiber depolarization) as in malignant hyperthermia or leaky (Ca 2+ dysregulation and depletion of Ca 2+ from the sarcoplasmic reticulum) RYR1 channels as in classic central core disease (Hern andez-Ochoa et al 2015). Autosomal recessive RYR1-related myopathies on the other hand, often result from a compound heterozygous missense variant in combination with a nonsense, splice-site, or frameshift variant (Klein et al 2012). These variants can cause excitation-contraction uncoupling in the severe recessive from of central core disease or loss of normal RYR1 expression as in multiminicore disease (Hern andez-Ochoa et al 2015).…”

RYR1‐related myopathies: a wide spectrum of phenotypes throughout life

“…Two recurrent pathogenic alleles were observed, the p.(Val4849Ile) mutation seen in one-third of the MHS families and possibly representing a founder mutation in the Dutch area, and a recurrent allele carrying three different missense mutations [p.(Ile1571Val), p.(Arg3366His) and p.(Tyr3933Cys)] detected in five different AR families. This combination of mutations on one allele has been observed before [22] and is very likely to be pathogenic because it is quite frequent in the Dutch population with recessive RYR1-related myopathy. It is unclear whether one of the mutations is causative or whether a combination of two or all three is causative.…”

RYR1 causing distal myopathy

“…The ability to sequencing the entirety of RYR1 gene has dramatically increased the number of identified mutations and the awareness of many more clinical phenotypes and different modes of inheritance. Dominantly inherited RYR1 gene mutations yielding MHS and central core pathology are usually linked with heterozygous missense mutations in hotspot regions (Klein et al 2012;Snoeck et al 2015). Recessive RYR1 myopathies are usually due to a heterozygous missense variant in trans with a null or frameshift variant and can be located throughout the entirety of the coding region (Jungbluth et al 2002;Monnier et al 2008;Klein et al 2012).…”