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Common genetic etiology between “multiple sclerosis-like” single-gene disorders and familial multiple sclerosis

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Abstract

Several single-gene disorders with clinical and radiological characteristics similar to those observed in multiple sclerosis (MS) patients have been described. To evaluate whether this phenotypic overlap can be ascribed to a common genetic etiology, 28 genes known to present pathogenic mutations for 24 of these disorders were sequenced in 270 MS patients. All identified variants were genotyped in 2131 MS cases and 830 healthy controls, and those exclusively observed in patients were assessed for segregation within families. This analysis identified 9 rare variants in 6 genes segregating with disease in 13 families. Four different mutations were identified in CYP27A1, including a reported pathogenic mutation for cerebrotendinous xanthomatosis (p.R405W), which was observed in six patients from a multi-incident family, three diagnosed with MS, two with an undefined neurological disease and one seemingly healthy. A LYST p.V1678A and a PDHA1 p.K387Q mutation were both observed in five MS patients from three separate multi-incident families. In addition, CLCN2 p.V174G, GALC p.D162E and POLG p.R361G were each identified in two MS patients from one family. This study suggests a shared genetic etiology between MS and the characterized single-gene disorders, and highlights cholesterol metabolism and the synthesis of oxysterols as important biological mechanisms for familial MS.

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Acknowledgements

We are grateful to all individuals who generously participated in this study. We thank Kevin Atkins for data collection and extraction. This research was undertaken thanks to funding from the Canada Research Chair (950-228408) and Canada Excellence Research Chair (214444) programs, Canadian Institutes of Health Research (MOP-137051), Vancouver Coastal Health Research Institute, the Milan & Maureen Ilich Foundation (11-32095000), and the Vancouver Foundation (ADV14-1597).

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  1. Division of Neurology, Faculty of Medicine, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada

    Anthony L. Traboulsee & A. Dessa Sadovnick

  2. Department of Medical Genetics, University of British Columbia, Vancouver, Canada

    A. Dessa Sadovnick, Mary Encarnacion, Cecily Q. Bernales, Irene M. Yee, Maria G. Criscuoli & Carles Vilariño-Güell

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  1. Anthony L. Traboulsee
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Correspondence to Carles Vilariño-Güell.

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Traboulsee, A.L., Sadovnick, A.D., Encarnacion, M. et al. Common genetic etiology between “multiple sclerosis-like” single-gene disorders and familial multiple sclerosis. Hum Genet 136, 705–714 (2017). https://doi.org/10.1007/s00439-017-1784-9

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