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However, the exact pathogenicity and clinical significance of these mutations remain unclear. Here, we aimed to determine the role of <jats:italic>CHCHD10<\/jats:italic> mutations in ALS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed 4,365 whole genome sequenced ALS patients and 1,832 controls from 7 different countries and examined all nonsynonymous single nucleotide variants in <jats:italic>CHCHD10.<\/jats:italic> These were tested for association with ALS, independently and in aggregate using several genetic burden tests (including sequence kernel association test [SKAT], optimal unified test [SKAT\u2010O], and Firth logistic regression).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 3 new variants in cases, but only 1 was ALS\u2010specific. Also, 1 control\u2010specific mutation was identified. There was no increased burden of rare coding mutations among ALS patients compared to controls (<jats:italic>p<\/jats:italic>\u2009=\u20090.86, <jats:italic>p<\/jats:italic>\u2009=\u20090.86, and <jats:italic>p<\/jats:italic>\u2009=\u20090.88 for SKAT, SKAT\u2010O, and Firth, respectively). The few carriers with potential pathogenic <jats:italic>CHCHD10<\/jats:italic> mutations exhibited a slowly progressive ALS\u2010like phenotype with atypical features such as myopathy and deafness.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>\n<jats:italic>CHCHD10<\/jats:italic> mutations seem to be a far less prevalent cause of pure ALS than previously suggested, and instead appear related to more complex phenotypes. There appears to be insufficient evidence for the pathogenicity of most previously reported variants in pure ALS. This study shows that routine testing for <jats:italic>CHCHD10<\/jats:italic> mutations in pure ALS is not recommended and illustrates the importance of sufficient genetic and functional evidence in establishing pathogenicity of genetic variants. Ann Neurol 2018;83:110\u2013116<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25273","type":"journal-article","created":{"date-parts":[[2018,7,17]],"date-time":"2018-07-17T06:34:44Z","timestamp":1531809284000},"page":"110-116","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["<i>CHCHD10<\/i> variants in amyotrophic lateral sclerosis: Where is the evidence?"],"prefix":"10.1002","volume":"84","author":[{"name":"Project MinE ALS Sequencing 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