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

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

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.

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