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Precise genetic diagnosis remains challenging.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The aim of this study was to use a whole\u2010exome sequencing approach to study a large, highly consanguineous Italian family in order to identify a new gene correlated with pure cerebellar ataxia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Sequencing excluded the presence of mutations in known\u2010related genes but revealed a homozygous missense variant in\n                      <jats:italic>CLIC5<\/jats:italic>\n                      ; however in\u00a0vivo analysis of a\n                      <jats:italic>CLIC5<\/jats:italic>\n                      KO mouse model showed vestibular dysfunction without cerebellar involvement, suggesting that\n                      <jats:italic>CLIC5<\/jats:italic>\n                      is not directly involved in pure cerebellar ataxia onset. Further analysis identified two compound heterozygous variants in\n                      <jats:italic>NEFM<\/jats:italic>\n                      , and\n                      <jats:italic>in silico<\/jats:italic>\n                      analysis showed that they dysregulate NEFM phosphorylation. Phosphorylation of neurofilaments and subsequent formation of aggregates has already been linked to conditions such as ageffing and neurodegeneration. Moreover, in\u00a0vivo studies on mice transgenic for human\n                      <jats:italic>NEFM<\/jats:italic>\n                      have correlated NEFM phosphorylation and aggregation with neurodegeneration. Finally, neurofilaments have been proposed to be correlated to ataxia and autoimmune cerebellar ataxia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We therefore propose\n                      <jats:italic>NEFM<\/jats:italic>\n                      as a possible new candidate gene for hereditary cerebellar ataxia. These findings could be useful for advancing the genetic diagnosis of hereditary pure cerebellar ataxia, possibly enabling the screening of healthy carriers.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mgg3.70199","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T03:47:13Z","timestamp":1774928833000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exclusion of\n                    <scp>CLIC5<\/scp>\n                    as a Candidate Gene and Identification of\n                    <scp>NEFM<\/scp>\n                    as a Possible Novel Gene Correlated With Autosomal Recessive Pure Cerebellar Ataxia in a Highly Consanguineous Family"],"prefix":"10.1002","volume":"14","author":[{"given":"Paolo Enrico","family":"Maltese","sequence":"first","affiliation":[{"name":"MAGI'S LAB  Rovereto Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0666-9616","authenticated-orcid":false,"given":"Gabriele","family":"Bonetti","sequence":"additional","affiliation":[{"name":"MAGI'S LAB  Rovereto Italy"},{"name":"Department of Pharmaceutical Sciences University of Perugia  Perugia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Manara","sequence":"additional","affiliation":[{"name":"MAGI'S LAB  Rovereto Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedetta","family":"Tanzi","sequence":"additional","affiliation":[{"name":"MAGI'S LAB  Rovereto Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Bernini","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry, and Pharmacy University of Siena  Siena Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark A.","family":"Berryman","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Ohio University  Athens Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soichi","family":"Tanda","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Ohio University  Athens Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corinne","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Ohio University  Athens Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Casagrande","sequence":"additional","affiliation":[{"name":"Neurology Unit, Rovereto Hospital  Trento Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3887-936X","authenticated-orcid":false,"given":"Amanda","family":"Ferrero","sequence":"additional","affiliation":[{"name":"Fondazione Serena Centro Clinico NeMO Trento, APSS  Trento Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salvatore","family":"Stano","sequence":"additional","affiliation":[{"name":"Fondazione Serena Centro Clinico NeMO Trento, APSS  Trento Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riccardo","family":"Zuccarino","sequence":"additional","affiliation":[{"name":"Fondazione Serena Centro Clinico NeMO Trento, APSS  Trento Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Barp","sequence":"additional","affiliation":[{"name":"Fondazione Serena Centro Clinico NeMO Trento, APSS  Trento Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pietro","family":"Chiurazzi","sequence":"additional","affiliation":[{"name":"Medicina Genomica, Dipartimento di Scienze Della Vita e sanit\u00e0 Pubblica Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"},{"name":"UOC Genetica Medica, Fondazione Policlinico Universitario \u2018A. 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