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© 2022 by the authors. 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/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models.

Details

Title
Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis
Author
Horjus, Julia 1 ; Tineke van Mourik-Banda 1 ; Heerings, Marco A P 1   VIAFID ORCID Logo  ; Hakobjan, Marina 1 ; Ward De Witte 1 ; Heersema, Dorothea J 2 ; Jansen, Anne J 3 ; Strijbis, Eva M M 4   VIAFID ORCID Logo  ; de Jong, Brigit A 5 ; Slettenaar, Astrid E J 6 ; Esther M P E Zeinstra 7 ; Hoogervorst, Erwin L J 8 ; Franke, Barbara 9 ; Wiebe Kruijer 10 ; Jongen, Peter J 11   VIAFID ORCID Logo  ; Visser, Leo J 12 ; Poelmans, Geert 1 

 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands 
 Department of Neurology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands 
 Department of Neurology, Bravis Hospital, 4708 AE Bergen op Zoom, The Netherlands 
 Department of Neurology, Amsterdam UMC, location VUmc, 1081 HV Amsterdam, The Netherlands 
 Department of Neurology, MS Center Amsterdam, Amsterdam UMC, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands 
 Department of Neurology, Medisch Spectrum Twente, 7512 KZ Enschede, The Netherlands 
 Department of Neurology, Isala Hospital, 7943 KC Meppel, The Netherlands 
 Department of Neurology, St. Antoniusziekenhuis, 3435 CM Nieuwegein, The Netherlands 
 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, 6525 GD Nijmegen, The Netherlands; Department of Psychiatry, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands 
10  Independent Life Science Consultant, 3831 CE Leusden, The Netherlands 
11  MS4 Research Institute, 6522 KJ Nijmegen, The Netherlands; Department of Community & Occupational Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands 
12  Department of Neurology, St. Elisabeth-Tweesteden Hospital, 5022 GC Tilburg, The Netherlands; Department of Care Ethics, University of Humanistic Studies, 3512 HD Utrecht, The Netherlands 
First page
11461
Publication year
2022
Publication date
2022
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2724285867
Copyright
© 2022 by the authors. 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/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.