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An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients
- Source :
- Genes, Vol 12, Iss 1607, p 1607 (2021), Genes (Basel) (2021). doi:10.3390/genes12101607, info:cnr-pdr/source/autori:Nadia Barizzone, Rachele Cagliani, Chiara Basagni, Ferdinando Clarelli, Laura Mendozzi, Cristina Agliardi, Diego Forni, Martina Tosi, Elisabetta Mascia, Francesco Favero, Davide Corà, Lucia Corrado, Melissa Sorosina, Federica Esposito, Miriam Zuccalà, Domizia Vecchio, Maria Liguori, Cristoforo Comi, Giancarlo Comi, Vittorio Martinelli, Massimo Filippi, Maurizio Leone, Filippo Martinelli-Boneschi, Domenico Caputo, Manuela Sironi, Franca Rosa Guerini and Sandra D'Alfonso/titolo:An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients/doi:10.3390%2Fgenes12101607/rivista:Genes (Basel)/anno:2021/pagina_da:/pagina_a:/intervallo_pagine:/volume, Genes, Volume 12, Issue 10
- Publication Year :
- 2021
- Publisher :
- MDPI AG, 2021.
-
Abstract
- 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.
- Subjects :
- Adult
Male
DNA Copy Number Variations
Genetic Linkage
multiple sclerosis
multiplex families
linkage study
NGS
rare variants
Biology
QH426-470
Article
Multiple sclerosis
03 medical and health sciences
0302 clinical medicine
Missing heritability problem
Genetic linkage
Exome Sequencing
medicine
Genetics
Humans
Multiplex
Genetic Predisposition to Disease
Gene
Exome
Genetics (clinical)
Genetic Association Studies
030304 developmental biology
Aged
Linkage study
Whole genome sequencing
Aged, 80 and over
0303 health sciences
Whole Genome Sequencing
Genome, Human
High-Throughput Nucleotide Sequencing
Rare variants
Heritability
Middle Aged
medicine.disease
Pedigree
Italy
Multiplex families
Female
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20734425
- Volume :
- 12
- Issue :
- 1607
- Database :
- OpenAIRE
- Journal :
- Genes
- Accession number :
- edsair.doi.dedup.....8f43adb75e99e528ad64b23d13dd7f69
- Full Text :
- https://doi.org/10.3390/genes12101607