{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:51:06Z","timestamp":1787028666874,"version":"build-2736575974"},"reference-count":38,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T00:00:00Z","timestamp":1770681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Variants in the ryanodine receptor 1 (RYR1) gene have been linked to a range of disorders, from congenital myopathy to adult-onset manifestations, with phenotypes varying from mild to severe. Methods: A retrospective review was conducted on an Israeli cohort of 36 individuals with RYR1 variants, identified through genetic testing as part of a national collaboration among multiple pediatric and adult neuromuscular clinics. Clinical features, molecular data, laboratory results, electromyographic findings, and muscle histology were analyzed. Each variant was classified according to its respective domain within the RYR1 gene. Results: Thirty-six cases were included in the analysis; 31 were from 11 unrelated families, and 5 were sporadic. Nine individuals were asymptomatic with normal CK levels. Most of the 27 affected patients presented with variable degrees of perinatal weakness, often accompanied by respiratory impairment or arthrogryposis. Weakness was predominantly proximal, with clinical courses that included deterioration, improvement, or stabilization. Three cases of King\u2013Denborough syndrome were identified. Additional presentations included malignant hyperthermia and, in isolated cases, periodic paralysis. Muscle biopsies demonstrated considerable histologic heterogeneity, including fiber-size variation, internal nuclei, multiminicores, and fibrosis or dystrophic features. The pathogenic RYR1 variants included five compound-heterozygous genotypes, two homozygous variants, and two heterozygous variants. There was a positive correlation between variants located in the Bsol domain and disease severity. Conclusions: This cohort confirms and expands the clinical and histological diversity associated with RYR1 variants in Israel. Variants in the Bsol domain appear to be indicative of disease severity.<\/jats:p>","DOI":"10.3390\/jcm15041388","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T12:07:06Z","timestamp":1770725226000},"page":"1388","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Clinical, Histological, and Genetic Spectrum of RYR1 Variants\u2014A Multi-Center Israeli Cohort Study"],"prefix":"10.3390","volume":"15","author":[{"given":"Mira","family":"Ginsberg","sequence":"first","affiliation":[{"name":"Pediatric Neuromuscular Clinic, Pediatric Neurology Unit, Wolfson Medical Center, Holon 5822012, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3794-0843","authenticated-orcid":false,"given":"Marina","family":"Michelson","sequence":"additional","affiliation":[{"name":"Pediatric Neuromuscular Clinic, Pediatric Neurology Unit, Wolfson Medical Center, Holon 5822012, Israel"},{"name":"Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7255-6276","authenticated-orcid":false,"given":"Sharon","family":"Aharoni","sequence":"additional","affiliation":[{"name":"Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Pediatric Neurology Unit, Schneider Children Medical Center, Petch-Tikva 49202, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liora","family":"Sagie","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Institute, Dana-Dwek Children\u2019s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Michaeli","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, Wolfson Medical Center, Holon 5822012, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ditza","family":"Rotenberg","sequence":"additional","affiliation":[{"name":"Independent Researcher, Ness-Ziona 740511, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitaly","family":"Finkelshtein","sequence":"additional","affiliation":[{"name":"Department of Neurology, Wolfson Medical Center, Holon 5822012, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keren","family":"Yosovich","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics, Wolfson Medical Center, Holon 5822012, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zohar","family":"Argov","sequence":"additional","affiliation":[{"name":"Hadassa Medical Center, Jerusalem 9112001, Israel"},{"name":"Faculty of Medicine, Hebrew University, Jerusalem 9112102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Nissenkorn","sequence":"additional","affiliation":[{"name":"Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Pediatric Neurology Unit, Wolfson Medical Center, Holon 5822012, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorit","family":"Lev","sequence":"additional","affiliation":[{"name":"Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Institute of Medical Genetics, Wolfson Medical Center, Holon 5822012, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7408-4652","authenticated-orcid":false,"given":"Menachem","family":"Sadeh","sequence":"additional","affiliation":[{"name":"Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Department of Neurology, Wolfson Medical Center, Holon 5822012, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron","family":"Dabby","sequence":"additional","affiliation":[{"name":"Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Department of Neurology, Wolfson Medical Center, Holon 5822012, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0031-6997(24)01312-7","article-title":"The sarcoplasmic reticulum Ca2+ channel\/ryanodine receptor: Modulation by endogenous effectors, drugs and disease states","volume":"49","author":"Zucchi","year":"1997","journal-title":"Pharmacol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"19225","DOI":"10.1073\/pnas.0504334102","article-title":"Interaction between the dihydropyridine receptor Ca2+ channel \u03b2-subunit and ryanodine receptor type 1 strengthens excitation-contraction coupling","volume":"102","author":"Cheng","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2122140119","DOI":"10.1073\/pnas.2122140119","article-title":"Molecular mechanism of the severe MH\/CCD variant Y522S in skeletal ryanodine receptor (RyR1) by cryo-EM","volume":"119","author":"Iyer","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1111\/ane.12885","article-title":"Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome","volume":"137","author":"Witting","year":"2018","journal-title":"Acta Neurol. Scand."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1111\/ene.12713","article-title":"RYR1-related myopathies: A wide spectrum of phenotypes throughout life","volume":"22","author":"Snoeck","year":"2015","journal-title":"Eur. J. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/s40478-014-0148-0","article-title":"Germline variants in RYR1 are associated with foetal akinesia deformation sequence\/lethal multiple pterygium syndrome","volume":"2","author":"McKie","year":"2014","journal-title":"Acta Neuropath. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.nmd.2013.03.008","article-title":"Variants in RYR1 are a common cause of exertional myalgia and rhabdomyolysis","volume":"23","author":"Dlamini","year":"2013","journal-title":"Neuromuscul. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s40478-022-01357-0","article-title":"Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: An Italian population study","volume":"10","author":"Fusto","year":"2022","journal-title":"Acta Neuropath. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"E1544","DOI":"10.1002\/humu.21278","article-title":"Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion","volume":"31","author":"Clarke","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1093\/brain\/awm096","article-title":"Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies","volume":"130","author":"Zhou","year":"2007","journal-title":"Brain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/1750-1172-8-117","article-title":"Genotype-phenotype correlations in recessive RYR1-related myopathies","volume":"8","author":"Amburgey","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1152\/physiolgenomics.00126.2016","article-title":"Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia","volume":"49","author":"Beam","year":"2017","journal-title":"Physiol. Genom."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1097\/ALN.0000000000000610","article-title":"Next-generation sequencing of RYR1 and CACNA1S in malignant hyperthermia and exertional heat illness","volume":"122","author":"Fiszer","year":"2015","journal-title":"Anesthesiology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.cell.2016.08.075","article-title":"Structural basis for gating and activation of RyR1","volume":"167","author":"Clarke","year":"2016","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101137","DOI":"10.1016\/j.gim.2024.101137","article-title":"Laboratory testing for preconception\/prenatal carrier screening: A technical standard of the American College of Medical Genetics and Genomics (ACMG)","volume":"26","author":"Guha","year":"2024","journal-title":"Genet. Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Attali, R., Aharoni, S., Treves, S., Rokach, O., Becker Cohen, M., Fellig, Y., Straussberg, R., Dor, T., Daana, M., and Mitrani-Rosenbaum, S. (2013). Variable myopathic presentation in a single family with novel skeletal RYR1 mutation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0069296"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s00401-012-1007-3","article-title":"Samaritan myopathy, an ultimately benign congenital myopathy, is caused by a RYR1 mutation","volume":"124","author":"Vassilopoulos","year":"2012","journal-title":"Acta Neuropathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.nmd.2009.12.005","article-title":"Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene","volume":"20","author":"Zhou","year":"2010","journal-title":"Neuromuscul. Disord."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1002\/humu.20356","article-title":"Mutations in RYR1 in malignant hyperthermia and central core disease","volume":"27","author":"Robinson","year":"2006","journal-title":"Hum. Mutat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1016\/j.nmd.2022.10.003","article-title":"Risk of malignant hyperthermia in patients carrying a variant in the skeletal muscle ryanodine receptor 1 gene","volume":"32","author":"Janssens","year":"2022","journal-title":"Neuromuscul. Disord."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1002\/mus.22009","article-title":"Dominant and recessive RYR1 mutations in adults with core lesions and mild muscle symptoms","volume":"44","author":"Duarte","year":"2011","journal-title":"Muscle Nerve"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1055\/s-0039-1698445","article-title":"Clinical Observation: Effect of a Second Transpositioned Variant in a Family with Autosomal Dominant Ryanodine Receptor-1\u2013Related Disease","volume":"9","author":"Avnon","year":"2020","journal-title":"J. Pediatr. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1186\/s40478-021-01254-y","article-title":"A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course","volume":"9","author":"Biancalana","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"104706","DOI":"10.1016\/j.ejmg.2023.104706","article-title":"Ryanodine receptor 1 related myasthenia like myopathy responsive to pyridostigmine","volume":"66","author":"Lester","year":"2023","journal-title":"Eur. J. Med. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103258","DOI":"10.1016\/j.scr.2023.103258","article-title":"Generation of two induced pluripotent stem cell lines from a 33-year-old central core disease patient with a heterozygous dominant c. 14145_14156delCTACTGGGACA (p. Asn4715_Asp4718del) deletion in the RYR1 gene","volume":"73","author":"Driver","year":"2023","journal-title":"Stem Cell Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e202313486","DOI":"10.1085\/jgp.202313486","article-title":"A novel, patient-derived RyR1 mutation impairs muscle function and calcium homeostasis in mice","volume":"156","author":"Benucci","year":"2024","journal-title":"J. Gen. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1152\/physrev.1997.77.3.699","article-title":"Ryanodine receptors of striated muscles: A complex channel capable of multiple interactions","volume":"77","author":"Protasi","year":"1997","journal-title":"Physiol. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"206","DOI":"10.2174\/1874467208666150507105105","article-title":"Essential roles of intracellular calcium release channels in muscle, brain, metabolism, and aging","volume":"8","author":"Santulli","year":"2015","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1038\/s41467-021-21141-3","article-title":"Pathological conformations of disease mutant ryanodine receptors revealed by cryo-EM","volume":"12","author":"Woll","year":"2021","journal-title":"Nat. Comm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e16471","DOI":"10.1111\/ene.16471","article-title":"A founder variant in the RYR1 gene is associated with hyperCKemia, myalgia and muscle cramps","volume":"32","author":"Iruzubieta","year":"2025","journal-title":"Eur. J. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1093\/brain\/awl077","article-title":"Central core disease is due to RYR1 mutations in more than 90% of patients","volume":"129","author":"Wu","year":"2006","journal-title":"Brain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1750-1172-2-31","article-title":"Multi-minicore disease","volume":"2","author":"Jungbluth","year":"2007","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/j.nmd.2017.05.016","article-title":"Common and variable clinical, histological, and imaging findings of recessive RYR1-related centronuclear myopathy patients","volume":"27","author":"Moreno","year":"2017","journal-title":"Neuromuscul. Disord."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1002\/humu.20231","article-title":"Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility","volume":"26","author":"Monnier","year":"2005","journal-title":"Hum. Mutat."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.nmd.2011.03.006","article-title":"King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene","volume":"21","author":"Dowling","year":"2011","journal-title":"Neuromuscul. Disord."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1002\/ajmg.a.20404","article-title":"A new mutation in the skeletal ryanodine receptor gene (RYR1) is potentially causative of malignant hyperthermia, central core disease, and severe skeletal malformation","volume":"124","author":"Rueffert","year":"2004","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1007\/s00415-018-9033-2","article-title":"Correlation of phenotype with genotype and protein structure in RYR1-related disorders","volume":"265","author":"Todd","year":"2018","journal-title":"J. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1212\/WNL.0000000000207723","article-title":"Long-term Natural History of Pediatric Dominant and Recessive RYR1-Related Myopathy","volume":"101","author":"Sarkozy","year":"2023","journal-title":"Neurology"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/4\/1388\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T12:35:11Z","timestamp":1770726911000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/4\/1388"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,10]]},"references-count":38,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["jcm15041388"],"URL":"https:\/\/doi.org\/10.3390\/jcm15041388","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,10]]}}}