Genes (Jan 2023)
Using Cluster Analysis to Overcome the Limits of Traditional Phenotype–Genotype Correlations: The Example of <i>RYR1</i>-Related Myopathies
- Claudia Dosi,
- Anna Rubegni,
- Jacopo Baldacci,
- Daniele Galatolo,
- Stefano Doccini,
- Guja Astrea,
- Angela Berardinelli,
- Claudio Bruno,
- Giorgia Bruno,
- Giacomo Pietro Comi,
- Maria Alice Donati,
- Maria Teresa Dotti,
- Massimiliano Filosto,
- Chiara Fiorillo,
- Fabio Giannini,
- Gian Luigi Gigli,
- Marina Grandis,
- Diego Lopergolo,
- Francesca Magri,
- Maria Antonietta Maioli,
- Alessandro Malandrini,
- Roberto Massa,
- Sabrina Matà,
- Federico Melani,
- Sonia Messina,
- Andrea Mignarri,
- Maurizio Moggio,
- Elena Maria Pennisi,
- Elena Pegoraro,
- Giulia Ricci,
- Michele Sacchini,
- Angelo Schenone,
- Simone Sampaolo,
- Monica Sciacco,
- Gabriele Siciliano,
- Giorgio Tasca,
- Paola Tonin,
- Rossella Tupler,
- Mariarosaria Valente,
- Nila Volpi,
- Denise Cassandrini,
- Filippo Maria Santorelli
Affiliations
- Claudia Dosi
- IRCCS Fondazione Stella Maris, 56128 Pisa, Italy
- Anna Rubegni
- IRCCS Fondazione Stella Maris, 56128 Pisa, Italy
- Jacopo Baldacci
- Kode Data Analysis s.r.l., 56128 Pisa, Italy
- Daniele Galatolo
- IRCCS Fondazione Stella Maris, 56128 Pisa, Italy
- Stefano Doccini
- IRCCS Fondazione Stella Maris, 56128 Pisa, Italy
- Guja Astrea
- IRCCS Fondazione Stella Maris, 56128 Pisa, Italy
- Angela Berardinelli
- IRCCS C. Mondino Foundation, 27100 Pavia, Italy
- Claudio Bruno
- Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
- Giorgia Bruno
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 81100 Naples, Italy
- Giacomo Pietro Comi
- Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
- Maria Alice Donati
- Metabolic Disease Unit, AOU Meyer Children Hospital, 50139 Florence, Italy
- Maria Teresa Dotti
- Unit of Neurology and Neurometabolic Diseases, Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy
- Massimiliano Filosto
- Department of Clinical and Experimental Sciences, University of Brescia, NeMO-Brescia Clinical Center for Neuromuscular Diseases, 25064 Brescia, Italy
- Chiara Fiorillo
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health—DINOGMI, University of Genova, 16147 Genova, Italy
- Fabio Giannini
- Unit of Neurology and Neurometabolic Diseases, Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy
- Gian Luigi Gigli
- Neurology Unit, Department of Neurosciences, University Hospital of Udine, 33100 Udine, Italy
- Marina Grandis
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health—DINOGMI, University of Genova, 16147 Genova, Italy
- Diego Lopergolo
- Unit of Neurology and Neurometabolic Diseases, Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy
- Francesca Magri
- Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit, 20122 Milan, Italy
- Maria Antonietta Maioli
- Centro Sclerosi Multipla, ASL Cagliari, 09047 Cagliari, Italy
- Alessandro Malandrini
- Unit of Neurology and Neurometabolic Diseases, Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy
- Roberto Massa
- Neuromuscular Diseases Unit, Department of Systems Medicine, Tor Vergata University of Rome, 00133 Rome, Italy
- Sabrina Matà
- Careggi University Hospital, Neurology Unit, 50134 Florence, Italy
- Federico Melani
- Pediatric Neurology, AOU Meyer Children Hospital, 50139 Florence, Italy
- Sonia Messina
- Unit of Neurology and Neuromuscular Disorders, Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy
- Andrea Mignarri
- Unit of Neurology and Neurometabolic Diseases, Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy
- Maurizio Moggio
- Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Diseases Unit, Department of Neuroscience, 20122 Milan, Italy
- Elena Maria Pennisi
- Neuromuscular Diseases Center, Neurology Unit, San Filippo Neri Hospital, 00135 Rome, Italy
- Elena Pegoraro
- Department of Neurosciences, University of Padova, 35122 Padova, Italy
- Giulia Ricci
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
- Michele Sacchini
- Metabolic Disease Unit, AOU Meyer Children Hospital, 50139 Florence, Italy
- Angelo Schenone
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health—DINOGMI, University of Genova, 16147 Genova, Italy
- Simone Sampaolo
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 81100 Naples, Italy
- Monica Sciacco
- Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Diseases Unit, Department of Neuroscience, 20122 Milan, Italy
- Gabriele Siciliano
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
- Giorgio Tasca
- Unit of Neurology, Fondazione Policlinico Universitario A. Gemelli IRCSS, 00168 Rome, Italy
- Paola Tonin
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37129 Verona, Italy
- Rossella Tupler
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy
- Mariarosaria Valente
- Neurology Unit, Department of Neurosciences, University Hospital of Udine, 33100 Udine, Italy
- Nila Volpi
- Unit of Neurology and Neurometabolic Diseases, Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy
- Denise Cassandrini
- IRCCS Fondazione Stella Maris, 56128 Pisa, Italy
- Filippo Maria Santorelli
- IRCCS Fondazione Stella Maris, 56128 Pisa, Italy
- DOI
- https://doi.org/10.3390/genes14020298
- Journal volume & issue
-
Vol. 14,
no. 2
p. 298
Abstract
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–phenotype 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–phenotype correlations, we found clustering to overcome the limits of the “single-dimension” paradigm traditionally used to describe genotype–phenotype relationships.
Keywords