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Using Cluster Analysis to Overcome the Limits of Traditional Phenotype–Genotype Correlations: The Example of RYR1-Related Myopathies
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9956305/ https://www.ncbi.nlm.nih.gov/pubmed/36833224 http://dx.doi.org/10.3390/genes14020298 |
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author | Dosi, Claudia Rubegni, Anna Baldacci, Jacopo Galatolo, Daniele Doccini, Stefano Astrea, Guja Berardinelli, Angela Bruno, Claudio Bruno, Giorgia Comi, Giacomo Pietro Donati, Maria Alice Dotti, Maria Teresa Filosto, Massimiliano Fiorillo, Chiara Giannini, Fabio Gigli, Gian Luigi Grandis, Marina Lopergolo, Diego Magri, Francesca Maioli, Maria Antonietta Malandrini, Alessandro Massa, Roberto Matà, Sabrina Melani, Federico Messina, Sonia Mignarri, Andrea Moggio, Maurizio Pennisi, Elena Maria Pegoraro, Elena Ricci, Giulia Sacchini, Michele Schenone, Angelo Sampaolo, Simone Sciacco, Monica Siciliano, Gabriele Tasca, Giorgio Tonin, Paola Tupler, Rossella Valente, Mariarosaria Volpi, Nila Cassandrini, Denise Santorelli, Filippo Maria |
author_facet | Dosi, Claudia Rubegni, Anna Baldacci, Jacopo Galatolo, Daniele Doccini, Stefano Astrea, Guja Berardinelli, Angela Bruno, Claudio Bruno, Giorgia Comi, Giacomo Pietro Donati, Maria Alice Dotti, Maria Teresa Filosto, Massimiliano Fiorillo, Chiara Giannini, Fabio Gigli, Gian Luigi Grandis, Marina Lopergolo, Diego Magri, Francesca Maioli, Maria Antonietta Malandrini, Alessandro Massa, Roberto Matà, Sabrina Melani, Federico Messina, Sonia Mignarri, Andrea Moggio, Maurizio Pennisi, Elena Maria Pegoraro, Elena Ricci, Giulia Sacchini, Michele Schenone, Angelo Sampaolo, Simone Sciacco, Monica Siciliano, Gabriele Tasca, Giorgio Tonin, Paola Tupler, Rossella Valente, Mariarosaria Volpi, Nila Cassandrini, Denise Santorelli, Filippo Maria |
author_sort | Dosi, Claudia |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9956305 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99563052023-02-25 Using Cluster Analysis to Overcome the Limits of Traditional Phenotype–Genotype Correlations: The Example of RYR1-Related Myopathies Dosi, Claudia Rubegni, Anna Baldacci, Jacopo Galatolo, Daniele Doccini, Stefano Astrea, Guja Berardinelli, Angela Bruno, Claudio Bruno, Giorgia Comi, Giacomo Pietro Donati, Maria Alice Dotti, Maria Teresa Filosto, Massimiliano Fiorillo, Chiara Giannini, Fabio Gigli, Gian Luigi Grandis, Marina Lopergolo, Diego Magri, Francesca Maioli, Maria Antonietta Malandrini, Alessandro Massa, Roberto Matà, Sabrina Melani, Federico Messina, Sonia Mignarri, Andrea Moggio, Maurizio Pennisi, Elena Maria Pegoraro, Elena Ricci, Giulia Sacchini, Michele Schenone, Angelo Sampaolo, Simone Sciacco, Monica Siciliano, Gabriele Tasca, Giorgio Tonin, Paola Tupler, Rossella Valente, Mariarosaria Volpi, Nila Cassandrini, Denise Santorelli, Filippo Maria Genes (Basel) Article 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. MDPI 2023-01-23 /pmc/articles/PMC9956305/ /pubmed/36833224 http://dx.doi.org/10.3390/genes14020298 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Dosi, Claudia Rubegni, Anna Baldacci, Jacopo Galatolo, Daniele Doccini, Stefano Astrea, Guja Berardinelli, Angela Bruno, Claudio Bruno, Giorgia Comi, Giacomo Pietro Donati, Maria Alice Dotti, Maria Teresa Filosto, Massimiliano Fiorillo, Chiara Giannini, Fabio Gigli, Gian Luigi Grandis, Marina Lopergolo, Diego Magri, Francesca Maioli, Maria Antonietta Malandrini, Alessandro Massa, Roberto Matà, Sabrina Melani, Federico Messina, Sonia Mignarri, Andrea Moggio, Maurizio Pennisi, Elena Maria Pegoraro, Elena Ricci, Giulia Sacchini, Michele Schenone, Angelo Sampaolo, Simone Sciacco, Monica Siciliano, Gabriele Tasca, Giorgio Tonin, Paola Tupler, Rossella Valente, Mariarosaria Volpi, Nila Cassandrini, Denise Santorelli, Filippo Maria Using Cluster Analysis to Overcome the Limits of Traditional Phenotype–Genotype Correlations: The Example of RYR1-Related Myopathies |
title | Using Cluster Analysis to Overcome the Limits of Traditional Phenotype–Genotype Correlations: The Example of RYR1-Related Myopathies |
title_full | Using Cluster Analysis to Overcome the Limits of Traditional Phenotype–Genotype Correlations: The Example of RYR1-Related Myopathies |
title_fullStr | Using Cluster Analysis to Overcome the Limits of Traditional Phenotype–Genotype Correlations: The Example of RYR1-Related Myopathies |
title_full_unstemmed | Using Cluster Analysis to Overcome the Limits of Traditional Phenotype–Genotype Correlations: The Example of RYR1-Related Myopathies |
title_short | Using Cluster Analysis to Overcome the Limits of Traditional Phenotype–Genotype Correlations: The Example of RYR1-Related Myopathies |
title_sort | using cluster analysis to overcome the limits of traditional phenotype–genotype correlations: the example of ryr1-related myopathies |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9956305/ https://www.ncbi.nlm.nih.gov/pubmed/36833224 http://dx.doi.org/10.3390/genes14020298 |
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