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However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We examined whole\u2010genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n\u2009=\u2009314), secondary progressive multiple sclerosis (SPMS; n\u2009=\u2009587), RMS (n\u2009=\u20092,248), and healthy subjects (n\u2009=\u2009987) genotyped using the MS replication chip.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: <jats:italic>KIF5A<\/jats:italic> p.Ala361Val in spastic paraplegia 10; <jats:italic>MLC1<\/jats:italic> p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and <jats:italic>REEP1<\/jats:italic> c.606\u2009+\u200943G&gt;T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP\u2010related mutations in PPMS patients compared to controls (risk ratio [<jats:italic>RR<\/jats:italic>] <jats:italic>=<\/jats:italic> 1.95; 95% confidence interval [CI], 1.27\u20132.98; <jats:italic>p<\/jats:italic>\u2009=\u20090.002), as well as in SPMS patients compared to controls (<jats:italic>RR\u2009=\u2009<\/jats:italic>1.57; 95% CI, 1.18\u20132.10; <jats:italic>p<\/jats:italic>\u2009=\u20090.002). Importantly, this enrichment was not detected in RMS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51\u201363<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25263","type":"journal-article","created":{"date-parts":[[2018,6,16]],"date-time":"2018-06-16T15:55:11Z","timestamp":1529164511000},"page":"51-63","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis"],"prefix":"10.1002","volume":"84","author":[{"given":"Xiaoming","family":"Jia","sequence":"first","affiliation":[{"name":"UCSF Weill Institute for Neurosciences University of California San Francisco San Francisco CA"},{"name":"Department of Neurology University of California San Francisco San Francisco CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lohith","family":"Madireddy","sequence":"additional","affiliation":[{"name":"UCSF Weill Institute for Neurosciences University of California San Francisco San Francisco CA"},{"name":"Department of 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Institute of Experimental Neurology (INSpe), Division of Neuroscience San Raffaele Scientific Institute Milan Italy"},{"name":"Department of Neurology and Neuro\u2010rehabilitation San Raffaele Scientific Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Comi","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology (INSpe), Division of Neuroscience San Raffaele Scientific Institute Milan Italy"},{"name":"Department of Neurology and Neuro\u2010rehabilitation San Raffaele Scientific Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Stuve","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurotherapeutics University of Texas Southwestern Medical Dallas TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1962-2574","authenticated-orcid":false,"given":"Yuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Menzies Institute for Medical Research University of Tasmania Hobart TAS Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Taylor","sequence":"additional","affiliation":[{"name":"Menzies Institute for Medical Research University of Tasmania Hobart TAS Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor","family":"Kilpatrick","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience The University of Melbourne Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Martinelli\u2010Boneschi","sequence":"additional","affiliation":[{"name":"Laboratory of Genomics of Neurological Diseases and Department of Neurology Policlinico San Donato Hospital and Scientific Institute San Donato Milanese Italy"},{"name":"Department of Biomedical Sciences for Health Universit\u00e0 degli Studi di Milano Milan Italy"},{"name":"Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology (INSpe), Division of Neuroscience San Raffaele Scientific Institute Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce A.C.","family":"Cree","sequence":"additional","affiliation":[{"name":"UCSF Weill Institute for Neurosciences University of California San Francisco San Francisco CA"},{"name":"Department of Neurology University of California San Francisco San Francisco CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge R.","family":"Oksenberg","sequence":"additional","affiliation":[{"name":"UCSF Weill Institute for Neurosciences University of California San Francisco San Francisco CA"},{"name":"Department of Neurology University of California San Francisco 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