Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.

Carles Vilariño‐Güell ,Laura Leyva,Weihong Song,Andrea Zauli,Jesús Ortega-Pinazo,Federica Esposito,Tobias Zrzavy,Zhe Wang,Patricia Urbaneja-Romero,Antonio Alcina,Elena Urcelay,Bruno Herculano,Elisabetta Mascia,Charbel Massaad,Angela Deutschländer,Jorge Mena,Alexander Zimprich,Denis Gris,Laura Espino-Paisán,Jordan Follett,Guillermo Izquierdo,Koen Vandenbroeck,Fuencisla Matesanz,Maria Criscuoli ,Filippo Martinelli Boneschi ,Jacqueline A Quandt ,Irene M Yee ,Eva M Reinthaler ,Alfredo Rodríguez Antigüedad ,Mary Joy Encarnacion ,Cecily Q Bernales ,Anthony Traboulsee ,A Dessa Sadovnick

doi:10.1371/journal.pgen.1008180

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.

Highlights

Multiple sclerosis (MS) is a common autoimmune disease of the central nervous system (CNS) affecting over two million people worldwide [1]
The majority of patients diagnosed with multiple sclerosis do not have a family history of disease, 13% report having a close relative diagnosed with multiple sclerosis
The cause of multiple sclerosis can be largely attributed to a single genetic variant that is transmitted through generations

Summary

Introduction

Multiple sclerosis (MS) is a common autoimmune disease of the central nervous system (CNS) affecting over two million people worldwide [1]. Given the large size of these case-control studies, risk variants that remain undiscovered to date are expected to be individually rare. We implemented high-throughput second generation sequencing technologies in multi-incident MS families for the identification of rare disease-causing variants. The majority of patients do not present a family history of MS, the prevalence of familial aggregation has been estimated at 12.6% globally [7] In these families, rare variants co-segregating with MS are likely to account for the highest attributable risk towards the disease; additional genetic and environmental factors are expected to play a significant role in the presentation of clinical symptoms, level of disability, disease progression, penetrance and onset age [8, 9]. Only one of these discoveries has been replicated [13], mutations responsible for Mendelian forms of MS

Methods

Results

Discussion

Conclusion