Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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
_version_ 1784894560453787648
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
work_keys_str_mv AT dosiclaudia usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT rubegnianna usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT baldaccijacopo usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT galatolodaniele usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT doccinistefano usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT astreaguja usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT berardinelliangela usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT brunoclaudio usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT brunogiorgia usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT comigiacomopietro usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT donatimariaalice usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT dottimariateresa usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT filostomassimiliano usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT fiorillochiara usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT gianninifabio usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT gigligianluigi usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT grandismarina usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT lopergolodiego usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT magrifrancesca usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT maiolimariaantonietta usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT malandrinialessandro usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT massaroberto usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT matasabrina usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT melanifederico usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT messinasonia usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT mignarriandrea usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT moggiomaurizio usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT pennisielenamaria usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT pegoraroelena usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT riccigiulia usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT sacchinimichele usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT schenoneangelo usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT sampaolosimone usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT sciaccomonica usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT sicilianogabriele usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT tascagiorgio usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT toninpaola usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT tuplerrossella usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT valentemariarosaria usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT volpinila usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT cassandrinidenise usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies
AT santorellifilippomaria usingclusteranalysistoovercomethelimitsoftraditionalphenotypegenotypecorrelationstheexampleofryr1relatedmyopathies