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However, approximately 60% of cases with axonal neuropathies (CMT2) still remain without a genetic diagnosis. We aimed at identifying novel disease genes responsible for CMT2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed whole exome sequencing and targeted next generation sequencing panel analyses on a cohort of CMT2 families with evidence for autosomal recessive inheritance. We also performed functional studies to explore the pathogenetic role of selected variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified rare, recessive variants in the <jats:italic>MYO9B<\/jats:italic> (myosin IX) gene in two families with CMT2. <jats:italic>MYO9B<\/jats:italic> has not yet been associated with a human disease. MYO9B is an unconventional single\u2010headed processive myosin motor protein with signaling properties, and, consistent with this, our results indicate that a variant occurring in the MYO9B motor domain impairs protein expression level and motor activity. Interestingly, a <jats:italic>Myo9b<\/jats:italic>\u2010null mouse has degenerating axons in sciatic nerves and optic nerves, indicating that MYO9B plays an essential role in both peripheral nervous system and central nervous system axons, respectively. The degeneration observed in the optic nerve prompted us to screen for <jats:italic>MYO9B<\/jats:italic> mutations in a cohort of patients with optic atrophy (OA). Consistent with this, we found compound heterozygous variants in one case with isolated OA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Novel or very rare variants in <jats:italic>MYO9B<\/jats:italic> are associated with CMT2 and isolated OA.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.15601","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T15:40:26Z","timestamp":1666194026000},"page":"511-526","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Mutations in <i>MYO9B<\/i> are associated with Charcot\u2013Marie\u2013Tooth disease type 2 neuropathies and isolated optic atrophy"],"prefix":"10.1111","volume":"30","author":[{"given":"Silvia","family":"Cipriani","sequence":"first","affiliation":[{"name":"Division of Neuroscience Institute of Experimental Neurology, IRCCS Ospedale San Raffaele  Milan 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