{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:48:09Z","timestamp":1760147289540,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T00:00:00Z","timestamp":1674432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health-Ricerca Corrente","award":["RF-2013-02359065"],"award-info":[{"award-number":["RF-2013-02359065"]}]},{"name":"5\u00d71000","award":["RF-2013-02359065"],"award-info":[{"award-number":["RF-2013-02359065"]}]},{"name":"Ministry of Health","award":["RF-2013-02359065"],"award-info":[{"award-number":["RF-2013-02359065"]}]},{"name":"Regione Toscana","award":["RF-2013-02359065"],"award-info":[{"award-number":["RF-2013-02359065"]}]},{"name":"FAS Salute 2018","award":["RF-2013-02359065"],"award-info":[{"award-number":["RF-2013-02359065"]}]},{"name":"InGene2.0","award":["RF-2013-02359065"],"award-info":[{"award-number":["RF-2013-02359065"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Thanks to advances in gene sequencing, RYR1-related myopathy (RYR1-RM) is now known to manifest itself in vastly heterogeneous forms, whose clinical interpretation is, therefore, highly challenging. We set out to develop a novel unsupervised cluster analysis method in a large patient population. The objective was to analyze the main RYR1-related characteristics to identify distinctive features of RYR1-RM and, thus, offer more precise genotype\u2013phenotype correlations in a group of potentially life-threatening disorders. We studied 600 patients presenting with a suspicion of inherited myopathy, who were investigated using next-generation sequencing. Among them, 73 index cases harbored variants in RYR1. In an attempt to group genetic variants and fully exploit information derived from genetic, morphological, and clinical datasets, we performed unsupervised cluster analysis in 64 probands carrying monoallelic variants. Most of the 73 patients with positive molecular diagnoses were clinically asymptomatic or pauci-symptomatic. Multimodal integration of clinical and histological data, performed using a non-metric multi-dimensional scaling analysis with k-means clustering, grouped the 64 patients into 4 clusters with distinctive patterns of clinical and morphological findings. In addressing the need for more specific genotype\u2013phenotype correlations, we found clustering to overcome the limits of the \u201csingle-dimension\u201d paradigm traditionally used to describe genotype\u2013phenotype relationships.<\/jats:p>","DOI":"10.3390\/genes14020298","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T03:21:54Z","timestamp":1674616914000},"page":"298","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Using Cluster Analysis to Overcome the Limits of Traditional Phenotype\u2013Genotype Correlations: The Example of RYR1-Related Myopathies"],"prefix":"10.3390","volume":"14","author":[{"given":"Claudia","family":"Dosi","sequence":"first","affiliation":[{"name":"IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0484-3799","authenticated-orcid":false,"given":"Anna","family":"Rubegni","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacopo","family":"Baldacci","sequence":"additional","affiliation":[{"name":"Kode Data Analysis s.r.l., 56128 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9402-2910","authenticated-orcid":false,"given":"Daniele","family":"Galatolo","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5534-8253","authenticated-orcid":false,"given":"Stefano","family":"Doccini","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guja","family":"Astrea","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4645-8055","authenticated-orcid":false,"given":"Angela","family":"Berardinelli","sequence":"additional","affiliation":[{"name":"IRCCS C. Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Bruno","sequence":"additional","affiliation":[{"name":"Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"},{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health\u2014DINOGMI, University of Genova, 16147 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9388-9336","authenticated-orcid":false,"given":"Giorgia","family":"Bruno","sequence":"additional","affiliation":[{"name":"Department of Advanced Medical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, 81100 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1383-5248","authenticated-orcid":false,"given":"Giacomo Pietro","family":"Comi","sequence":"additional","affiliation":[{"name":"Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy"},{"name":"Foundation IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Neurology Unit, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Alice","family":"Donati","sequence":"additional","affiliation":[{"name":"Metabolic Disease Unit, AOU Meyer Children Hospital, 50139 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Teresa","family":"Dotti","sequence":"additional","affiliation":[{"name":"Unit of Neurology and Neurometabolic Diseases, Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2852-7512","authenticated-orcid":false,"given":"Massimiliano","family":"Filosto","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Sciences, University of Brescia, NeMO-Brescia Clinical Center for Neuromuscular Diseases, 25064 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9027-343X","authenticated-orcid":false,"given":"Chiara","family":"Fiorillo","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health\u2014DINOGMI, University of Genova, 16147 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"Giannini","sequence":"additional","affiliation":[{"name":"Unit of Neurology and Neurometabolic Diseases, Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gian Luigi","family":"Gigli","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Neurosciences, University Hospital of Udine, 33100 Udine, Italy"},{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6637-4425","authenticated-orcid":false,"given":"Marina","family":"Grandis","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health\u2014DINOGMI, University of Genova, 16147 Genova, Italy"},{"name":"IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2256-0482","authenticated-orcid":false,"given":"Diego","family":"Lopergolo","sequence":"additional","affiliation":[{"name":"Unit of Neurology and Neurometabolic Diseases, Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Magri","sequence":"additional","affiliation":[{"name":"Foundation IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Neurology Unit, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Antonietta","family":"Maioli","sequence":"additional","affiliation":[{"name":"Centro Sclerosi Multipla, ASL Cagliari, 09047 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Malandrini","sequence":"additional","affiliation":[{"name":"Unit of Neurology and Neurometabolic Diseases, Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Massa","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases Unit, Department of Systems Medicine, Tor Vergata University of Rome, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Mat\u00e0","sequence":"additional","affiliation":[{"name":"Careggi University Hospital, Neurology Unit, 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Melani","sequence":"additional","affiliation":[{"name":"Pediatric Neurology, AOU Meyer Children Hospital, 50139 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"Messina","sequence":"additional","affiliation":[{"name":"Unit of Neurology and Neuromuscular Disorders, Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Mignarri","sequence":"additional","affiliation":[{"name":"Unit of Neurology and Neurometabolic Diseases, Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurizio","family":"Moggio","sequence":"additional","affiliation":[{"name":"Foundation IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Diseases Unit, Department of Neuroscience, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0600-6855","authenticated-orcid":false,"given":"Elena Maria","family":"Pennisi","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases Center, Neurology Unit, San Filippo Neri Hospital, 00135 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7740-4156","authenticated-orcid":false,"given":"Elena","family":"Pegoraro","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of Padova, 35122 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Ricci","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Sacchini","sequence":"additional","affiliation":[{"name":"Metabolic Disease Unit, AOU Meyer Children Hospital, 50139 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2604-7830","authenticated-orcid":false,"given":"Angelo","family":"Schenone","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health\u2014DINOGMI, University of Genova, 16147 Genova, Italy"},{"name":"IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone","family":"Sampaolo","sequence":"additional","affiliation":[{"name":"Department of Advanced Medical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, 81100 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Sciacco","sequence":"additional","affiliation":[{"name":"Foundation IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Diseases Unit, Department of Neuroscience, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Siciliano","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0849-9144","authenticated-orcid":false,"given":"Giorgio","family":"Tasca","sequence":"additional","affiliation":[{"name":"Unit of Neurology, Fondazione Policlinico Universitario A. Gemelli IRCSS, 00168 Rome, Italy"},{"name":"John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle upon Tyne NE1 3BZ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Tonin","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37129 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3797-1789","authenticated-orcid":false,"given":"Rossella","family":"Tupler","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy"},{"name":"Department of Molecular Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariarosaria","family":"Valente","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Neurosciences, University Hospital of Udine, 33100 Udine, Italy"},{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nila","family":"Volpi","sequence":"additional","affiliation":[{"name":"Unit of Neurology and Neurometabolic Diseases, Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3556-8638","authenticated-orcid":false,"given":"Denise","family":"Cassandrini","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1359-9062","authenticated-orcid":false,"given":"Filippo Maria","family":"Santorelli","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Gonzalez-Quereda, L., Rodriguez, M.J., Diaz-Manera, J., Alonso-Perez, J., Gallardo, E., Nascimento, A., Ortez, C., Benito, D.N.-D., Olive, M., and Gonzalez-Mera, L. (2020). Targeted next-generation sequencing in a large cohort of genetically undiagnosed patients with neuromuscular disorders in Spain. Genes, 11.","DOI":"10.3390\/genes11050539"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s41591-018-0316-z","article-title":"A guide to deep learning in healthcare","volume":"25","author":"Esteva","year":"2019","journal-title":"Nat. Med."},{"key":"ref_3","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_4","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1002\/prot.25971","article-title":"Investigating dual Ca2+ modulation of the ryanodine receptor 1 by molecular dynamics simulation","volume":"88","author":"Zheng","year":"2020","journal-title":"Proteins"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1212\/WNL.55.11.1689","article-title":"A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy","volume":"55","author":"Scacheri","year":"2000","journal-title":"Neurology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1002\/ana.22119","article-title":"RYR1 mutations are a common cause of congenital myopathies with central nuclei","volume":"68","author":"Wilmshurst","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: Ajoint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13023-020-01384-x","article-title":"Preclinical model systems of ryanodine receptor 1-related myopathies and malignant hyperthermia: A comprehensive scoping review of works published 1990\u20132019","volume":"15","author":"Lawal","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1007\/s00415-019-09209-z","article-title":"The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations","volume":"266","author":"Knuiman","year":"2019","journal-title":"J. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1093\/bioinformatics\/btp543","article-title":"Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis","volume":"25","author":"Shen","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e352","DOI":"10.1212\/NXG.0000000000000352","article-title":"Next-generation sequencing approach to hyperCKemia: a2-year cohort study","volume":"5","author":"Rubegni","year":"2019","journal-title":"Neurol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s40478-014-0100-3","article-title":"MotorPlex provides accurate variant detection across large muscle genes both in single myopathic patients and in pools of DNA samples","volume":"2","author":"Savarese","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"981","DOI":"10.3389\/fneur.2018.00981","article-title":"Next generation molecular diagnosis of hereditary spastic paraplegias: An Italian cross-sectional study","volume":"9","author":"Tessa","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1002\/humu.24024","article-title":"Bi-allelic mutations in HARS1 severely impair histidyl-tRNA synthetase expression and enzymatic activity causing a novel multisystem ataxic syndrome","volume":"41","author":"Galatolo","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cox, T.F., and Cox, M.A.A. (2001). Multidimensional Scaling, Chapman and Hall.","DOI":"10.1201\/9780367801700"},{"key":"ref_17","unstructured":"Coxon, A.P.M., and Jackson, J.E. (2022, November 03). The User\u2019s Guide to Multidimensional Scaling: With Special Reference to the MDS(X) Library of Computer Programs. Heinemann Educational Books. Available online: https:\/\/www.tandfonline.com\/doi\/epdf\/10.1080\/00401706.1985.10488019."},{"key":"ref_18","unstructured":"Tan, P.N., and Steinbach, M.K. (2018). Introduction to Data Mining, Pearson. [2nd ed.]."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3439","DOI":"10.1007\/s11665-016-2173-6","article-title":"Study on high-temperature flow behavior and substructure and texture evolution of TA15 titanium alloy","volume":"25","author":"Li","year":"2016","journal-title":"J. Mater. Eng. Perform."},{"key":"ref_20","first-page":"1","article-title":"Community Ecology Package: Ordination, diversity and dissimilarities","volume":"2","author":"Oksanen","year":"2019","journal-title":"Community Ecol. Packag."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1007\/s13311-018-00677-1","article-title":"Ryanodine receptor 1-related myopathies: Diagnostic and therapeutic approaches","volume":"15","author":"Lawal","year":"2018","journal-title":"Neurotherapeutics"},{"key":"ref_22","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_23","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1212\/WNL.0000000000002800","article-title":"The genetic basis of undiagnosed muscular dystrophies and myopathies. Results from 504 patients","volume":"87","author":"Savarese","year":"2016","journal-title":"Neurology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1002\/ajmg.a.61025","article-title":"Homozygous\/compound heterozygote RYR1 gene variants: Expanding the clinical spectrum","volume":"179","author":"Alkhunaizi","year":"2019","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"118","DOI":"10.3389\/fneur.2018.00118","article-title":"Novel variants in individuals with RYR1-related congenital myopathies: Genetic, laboratory, and clinical findings","volume":"9","author":"Todd","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1111\/ene.12713","article-title":"RYR1-related myopathies: Awide spectrum of phenotypes throughout life","volume":"22","author":"Snoeck","year":"2015","journal-title":"Eur. J. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.nmd.2013.03.008","article-title":"Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis","volume":"23","author":"Dlamini","year":"2013","journal-title":"Neuromuscul. Disord."},{"key":"ref_28","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":"Haugarvoll","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1002\/humu.22056","article-title":"Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies","volume":"33","author":"Klein","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"54","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 Neuropathol. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4457","DOI":"10.1038\/s41598-021-84003-4","article-title":"Combined unsupervised-supervised machine learning for phenotyping complex diseases with its application to obstructive sleep apnea","volume":"11","author":"Ma","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3784","DOI":"10.1016\/j.celrep.2019.02.105","article-title":"Transcriptomic Analysis of Single Isolated Myofibers Identifies miR-27a-3p and miR-142-3p as Regulators of Metabolism in Skeletal Muscle","volume":"26","author":"Chemello","year":"2019","journal-title":"Cell Rep."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/298\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:13:50Z","timestamp":1760120030000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/298"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,23]]},"references-count":32,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["genes14020298"],"URL":"https:\/\/doi.org\/10.3390\/genes14020298","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2023,1,23]]}}}