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Histological assessment of a muscle biopsy specimen was performed in 1 patient, and quantitative tremor analysis was carried out in 2 patients. Molecular modeling studies and biochemical assays were performed for both mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Two novel missense mutations in <jats:italic>MYBPC1<\/jats:italic> (p.E248K in family 1 and p.Y247H in family 2) were identified and shown to segregate perfectly with the myopathy\/tremor phenotype in the respective families. <jats:italic>MYBPC1<\/jats:italic> encodes slow myosin binding protein\u2010C (sMyBP\u2010C), a modular sarcomeric protein playing structural and regulatory roles through its dynamic interaction with actin and myosin filaments. The Y247H and E248K mutations are located in the NH<jats:sub>2<\/jats:sub>\u2010terminal M\u2010motif of sMyBP\u2010C. Both mutations result in markedly increased binding of the NH<jats:sub>2<\/jats:sub> terminus to myosin, possibly interfering with normal cross\u2010bridge cycling as the first muscle\u2010based step in tremor genesis. The clinical tremor features observed in all mutation carriers, together with the tremor physiology studies performed in family 2, suggest amplification by an additional central loop modulating the clinical tremor phenomenology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Here, we link two novel missense mutations in <jats:italic>MYBPC1<\/jats:italic> with a dominant, mild skeletal myopathy invariably associated with a distinctive tremor. The molecular, genetic, and clinical studies are consistent with a unique sarcomeric origin of the tremor, which we classify as \u201cmyogenic tremor.\u201d ANN NEUROL 2019<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25494","type":"journal-article","created":{"date-parts":[[2019,4,26]],"date-time":"2019-04-26T08:56:04Z","timestamp":1556268964000},"page":"129-142","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Novel mutations in <i>MYBPC1<\/i> are associated with myogenic tremor and mild myopathy"],"prefix":"10.1002","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0109-3312","authenticated-orcid":false,"given":"Janis","family":"Stavusis","sequence":"first","affiliation":[{"name":"Latvian Biomedical Research and Study Centre  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baiba","family":"Lace","sequence":"additional","affiliation":[{"name":"Latvian Biomedical Research 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