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One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We use whole exome sequencing (<jats:styled-content style=\"fixed-case\">WES<\/jats:styled-content>) to develop a clinically relevant approach to identify a subset of <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> patients harboring likely pathogenic mutations. In parallel, we assess if <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation can be used to screen for pathogenicity of novel variants since a methylation signature has been shown to associate with the pathogenic <jats:italic>C9orf72<\/jats:italic> expansion, but has not been explored for other <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> mutations. Australian patients identified with <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content>\u2010relevant variants were cross\u2010checked with population databases and case reports to critically assess whether they were \u201clikely causal,\u201d \u201cuncertain significance,\u201d or \u201cunlikely causal.\u201d<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Published <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> variants were identified in &gt;10% of patients; however, in only 3% of patients (4\/120) could these be confidently considered pathogenic (in <jats:italic><jats:styled-content style=\"fixed-case\">SOD<\/jats:styled-content>1<\/jats:italic> and <jats:italic><jats:styled-content style=\"fixed-case\">TARDBP<\/jats:styled-content><\/jats:italic>). We found no evidence for a differential <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation signature in these mutation carriers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The use of <jats:styled-content style=\"fixed-case\">WES<\/jats:styled-content> in a typical <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> clinic demonstrates a critical approach to variant assessment with the capability to combine cohorts to enhance the largely unknown genetic basis of <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.302","type":"journal-article","created":{"date-parts":[[2017,6,13]],"date-time":"2017-06-13T00:46:36Z","timestamp":1497314796000},"page":"418-428","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Whole exome sequencing and <scp>DNA<\/scp> methylation analysis in a clinical amyotrophic lateral sclerosis cohort"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1490-5930","authenticated-orcid":false,"given":"Fleur C.","family":"Garton","sequence":"first","affiliation":[{"name":"Queensland Brain Institute The University of Queensland St Lucia Queensland 4072 Australia"},{"name":"Institute for Molecular Bioscience The University of Queensland St Lucia Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beben","family":"Benyamin","sequence":"additional","affiliation":[{"name":"Queensland Brain Institute The University of Queensland St Lucia Queensland 4072 Australia"},{"name":"Institute for Molecular Bioscience The University of Queensland St Lucia Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiongyi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Queensland Brain Institute The University of Queensland St Lucia Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijun","family":"Liu","sequence":"additional","affiliation":[{"name":"Queensland Brain Institute The University of Queensland St Lucia Queensland 4072 Australia"},{"name":"Institute for Molecular Bioscience The University of Queensland St Lucia Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Gratten","sequence":"additional","affiliation":[{"name":"Queensland Brain Institute The University of Queensland St Lucia Queensland 4072 Australia"},{"name":"Institute for Molecular Bioscience The University of Queensland St Lucia Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjali K.","family":"Henders","sequence":"additional","affiliation":[{"name":"Queensland Brain Institute The University of Queensland St Lucia Queensland 4072 Australia"},{"name":"Institute for Molecular Bioscience The University of Queensland St Lucia Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zong\u2010Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Queensland Brain Institute The University of Queensland St Lucia Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janette","family":"Edson","sequence":"additional","affiliation":[{"name":"Queensland Brain Institute The University of Queensland St Lucia Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Furlong","sequence":"additional","affiliation":[{"name":"Queensland Brain Institute The University of Queensland St Lucia Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Morgan","sequence":"additional","affiliation":[{"name":"Reta Lila Weston Institute UCL Institute of Neurology London UK"},{"name":"Department of Molecular Neuroscience UCL Institute of Neurology London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Heggie","sequence":"additional","affiliation":[{"name":"UQ Centre for Clinical Research The University of Queensland Royal Brisbane &amp; 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