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An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients
Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease’s estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italia...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535321/ https://www.ncbi.nlm.nih.gov/pubmed/34681001 http://dx.doi.org/10.3390/genes12101607 |
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author | Barizzone, Nadia Cagliani, Rachele Basagni, Chiara Clarelli, Ferdinando Mendozzi, Laura Agliardi, Cristina Forni, Diego Tosi, Martina Mascia, Elisabetta Favero, Francesco Corà, Davide Corrado, Lucia Sorosina, Melissa Esposito, Federica Zuccalà, Miriam Vecchio, Domizia Liguori, Maria Comi, Cristoforo Comi, Giancarlo Martinelli, Vittorio Filippi, Massimo Leone, Maurizio Martinelli-Boneschi, Filippo Caputo, Domenico Sironi, Manuela Guerini, Franca Rosa D’Alfonso, Sandra |
author_facet | Barizzone, Nadia Cagliani, Rachele Basagni, Chiara Clarelli, Ferdinando Mendozzi, Laura Agliardi, Cristina Forni, Diego Tosi, Martina Mascia, Elisabetta Favero, Francesco Corà, Davide Corrado, Lucia Sorosina, Melissa Esposito, Federica Zuccalà, Miriam Vecchio, Domizia Liguori, Maria Comi, Cristoforo Comi, Giancarlo Martinelli, Vittorio Filippi, Massimo Leone, Maurizio Martinelli-Boneschi, Filippo Caputo, Domenico Sironi, Manuela Guerini, Franca Rosa D’Alfonso, Sandra |
author_sort | Barizzone, Nadia |
collection | PubMed |
description | Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease’s estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes—particularly mRNA transport—or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family. |
format | Online Article Text |
id | pubmed-8535321 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-85353212021-10-23 An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients Barizzone, Nadia Cagliani, Rachele Basagni, Chiara Clarelli, Ferdinando Mendozzi, Laura Agliardi, Cristina Forni, Diego Tosi, Martina Mascia, Elisabetta Favero, Francesco Corà, Davide Corrado, Lucia Sorosina, Melissa Esposito, Federica Zuccalà, Miriam Vecchio, Domizia Liguori, Maria Comi, Cristoforo Comi, Giancarlo Martinelli, Vittorio Filippi, Massimo Leone, Maurizio Martinelli-Boneschi, Filippo Caputo, Domenico Sironi, Manuela Guerini, Franca Rosa D’Alfonso, Sandra Genes (Basel) Article Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease’s estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes—particularly mRNA transport—or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family. MDPI 2021-10-13 /pmc/articles/PMC8535321/ /pubmed/34681001 http://dx.doi.org/10.3390/genes12101607 Text en © 2021 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 Barizzone, Nadia Cagliani, Rachele Basagni, Chiara Clarelli, Ferdinando Mendozzi, Laura Agliardi, Cristina Forni, Diego Tosi, Martina Mascia, Elisabetta Favero, Francesco Corà, Davide Corrado, Lucia Sorosina, Melissa Esposito, Federica Zuccalà, Miriam Vecchio, Domizia Liguori, Maria Comi, Cristoforo Comi, Giancarlo Martinelli, Vittorio Filippi, Massimo Leone, Maurizio Martinelli-Boneschi, Filippo Caputo, Domenico Sironi, Manuela Guerini, Franca Rosa D’Alfonso, Sandra An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients |
title | An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients |
title_full | An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients |
title_fullStr | An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients |
title_full_unstemmed | An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients |
title_short | An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients |
title_sort | investigation of the role of common and rare variants in a large italian multiplex family of multiple sclerosis patients |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535321/ https://www.ncbi.nlm.nih.gov/pubmed/34681001 http://dx.doi.org/10.3390/genes12101607 |
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