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To date, only a single <jats:italic>SCN4A<\/jats:italic> variant has been suggested to cause ET. In continuation of the previous report on the association between <jats:italic>SCN4A<\/jats:italic> and ET in a family from Spain, we validated the pathogenicity of a novel <jats:italic>SCN4A<\/jats:italic> variant and its involvement in ET in a second family affected by this disease. We recruited a Kurdish family with four affected members manifesting congenital tremor. Using whole\u2010exome sequencing, we identified a novel missense variant in <jats:italic>SCN4A<\/jats:italic>, NM_000334.4:c.4679C&gt;T; p.(Pro1560Leu), thus corroborating <jats:italic>SCN4A's<\/jats:italic> role in ET. The residue is highly conserved across vertebrates and the substitution is predicted to be pathogenic by various in silico tools. Western blotting and immunocytochemistry performed in cells derived from one of the patients showed reduced immunoreactivity of SCN4A as compared to control cells. The study provides supportive evidence for the role of <jats:italic>SCN4A<\/jats:italic> in the etiology of ET and expands the phenotypic spectrum of channelopathies to this neurological disorder.<\/jats:p>","DOI":"10.1002\/ajmg.a.62610","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T09:36:52Z","timestamp":1639647412000},"page":"1251-1258","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A novel missense variant of <scp><i>SCN4A<\/i><\/scp> co\u2010segregates with congenital essential tremor in a consanguineous Kurdish family"],"prefix":"10.1002","volume":"188","author":[{"given":"Maria","family":"Asif","sequence":"first","affiliation":[{"name":"Cologne Center for Genomics (CCG) University of Cologne, Faculty of Medicine and University Hospital Cologne  Cologne Germany"},{"name":"Center for Biochemistry, Medical Faculty University of Cologne  Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ionut Dragos","family":"Mocanu","sequence":"additional","affiliation":[{"name":"Center for Biochemistry, Medical Faculty University of Cologne  Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uzma","family":"Abdullah","sequence":"additional","affiliation":[{"name":"University Institute of Biochemistry and Biotechnology (UIBB) PMAS\u2010Arid Agriculture University  Rawalpindi Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"H\u00f6hne","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG) University of Cologne, Faculty of Medicine and University Hospital Cologne  Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janine","family":"Altm\u00fcller","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG) University of Cologne, Faculty of Medicine and University Hospital Cologne  Cologne Germany"},{"name":"Berlin Institute of Health at Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin Core Facility Genomics  Berlin Germany"},{"name":"Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC)  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ehtisham Ul Haq","family":"Makhdoom","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG) University of Cologne, Faculty of Medicine and University Hospital Cologne  Cologne Germany"},{"name":"Center for Biochemistry, Medical Faculty University of Cologne  Cologne Germany"},{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS  Faisalabad Pakistan"},{"name":"Neurochemicalbiology and Genetics Laboratory (NGL), Department of Physiology, Faculty of Life Sciences Government College University  Faisalabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Holger","family":"Thiele","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG) University of Cologne, Faculty of Medicine and University Hospital Cologne  Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shahid Mahmood","family":"Baig","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS  Faisalabad Pakistan"},{"name":"Pakistan Science Foundation (PSF)  Islamabad Pakistan"},{"name":"Department of Biological and Biomedical Sciences Aga Khan University  Karachi Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"N\u00fcrnberg","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG) University of Cologne, Faculty of Medicine and University Hospital Cologne  Cologne Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC) University of Cologne, Faculty of Medicine and University Hospital Cologne  Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6540-6314","authenticated-orcid":false,"given":"Luitgard","family":"Graul\u2010Neumann","sequence":"additional","affiliation":[{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Institut f\u00fcr Medizinische Genetik und Humangenetik  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1353-8809","authenticated-orcid":false,"given":"Muhammad Sajid","family":"Hussain","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG) University of Cologne, Faculty of Medicine and University Hospital Cologne  Cologne Germany"},{"name":"Center for Biochemistry, Medical Faculty University of Cologne  Cologne Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC) University of Cologne, Faculty of Medicine and University Hospital Cologne  Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,12,16]]},"reference":[{"issue":"11","key":"e_1_2_9_2_1","first-page":", S7","article-title":"Criteria for the diagnosis of essential tremor","volume":"54","author":"Bain P.","year":"2000","journal-title":"Neurology"},{"issue":"24","key":"e_1_2_9_3_1","first-page":"7111","article-title":"SCN4A pore mutation pathogenetically contributes to autosomal dominant essential tremor and may increase susceptibility to epilepsy","volume":"24","author":"Bergareche A.","year":"2015","journal-title":"Human Molecular Genetics"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c140062"},{"issue":"3","key":"e_1_2_9_5_1","first-page":"2","article-title":"Consensus statement of the Movement Disorder Society on Tremor. 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