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A deep intronic variant, <jats:italic>MME<\/jats:italic> c.1188+428A&gt;G (NM_000902.5), was identified through whole genome sequencing (WGS) of two Australian families with recessive inheritance of axonal CMT using the seqr platform. <jats:italic>MME<\/jats:italic> c.1188+428A&gt;G was detected in a homozygous state in Family 1, and in a compound heterozygous state with a known pathogenic <jats:italic>MME<\/jats:italic> variant (c.467del; p.Pro156Leufs*14) in Family 2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims<\/jats:title><jats:p>We aimed to determine the pathogenicity of the <jats:italic>MME<\/jats:italic> c.1188+428A&gt;G variant through segregation and splicing analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The splicing impact of the deep intronic <jats:italic>MME<\/jats:italic> variant c.1188+428A&gt;G was assessed using an in vitro exon\u2010trapping assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The exon\u2010trapping assay demonstrated that the <jats:italic>MME<\/jats:italic> c.1188+428A&gt;G variant created a novel splice donor site resulting in the inclusion of an 83\u2009bp pseudoexon between <jats:italic>MME<\/jats:italic> exons 12 and 13. The incorporation of the pseudoexon into <jats:italic>MME<\/jats:italic> transcript is predicted to lead to a coding frameshift and premature termination codon (PTC) in <jats:italic>MME<\/jats:italic> exon 14 (p.Ala397ProfsTer47). This PTC is likely to result in nonsense mediated decay (NMD) of <jats:italic>MME<\/jats:italic> transcript leading to a pathogenic loss\u2010of\u2010function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>To our knowledge, this is the first report of a pathogenic deep intronic <jats:italic>MME<\/jats:italic> variant causing CMT. This is of significance as deep intronic variants are missed using whole exome sequencing screening methods. Individuals with CMT should be reassessed for deep intronic variants, with splicing impacts being considered in relation to the potential pathogenicity of variants.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jns.12637","type":"journal-article","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T08:17:51Z","timestamp":1718093871000},"page":"262-274","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A deep intronic variant in <scp><i>MME<\/i><\/scp> causes autosomal recessive Charcot\u2013Marie\u2013Tooth neuropathy through aberrant splicing"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6926-0551","authenticated-orcid":false,"given":"Bianca R.","family":"Grosz","sequence":"first","affiliation":[{"name":"Northcott Neuroscience Laboratory ANZAC Research Institute  Sydney New South Wales Australia"},{"name":"The University of Sydney  Camperdown New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1864-8094","authenticated-orcid":false,"given":"Jevin M.","family":"Parmar","sequence":"additional","affiliation":[{"name":"Rare Disease Genetics and Functional Genomics Research Group, Harry Perkins Institute of Medical Research QEII Medical Centre  Nedlands Western Australia Australia"},{"name":"Centre for Medical Research, Faculty of Health and Medical Sciences The University of Western Australia  Perth Western Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8542-048X","authenticated-orcid":false,"given":"Melina","family":"Ellis","sequence":"additional","affiliation":[{"name":"Northcott Neuroscience Laboratory ANZAC Research Institute  Sydney New South Wales Australia"},{"name":"The University of Sydney  Camperdown New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4140-8622","authenticated-orcid":false,"given":"Samantha","family":"Bryen","sequence":"additional","affiliation":[{"name":"Centre for Population Genomics Garvan Institute of Medical Research, and UNSW Sydney  Sydney New South Wales Australia"},{"name":"Centre for Population Genomics Murdoch Children's Research Institute  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3147-8042","authenticated-orcid":false,"given":"Cas","family":"Simons","sequence":"additional","affiliation":[{"name":"Centre for Population Genomics Garvan Institute of Medical Research, and UNSW Sydney  Sydney New South Wales Australia"},{"name":"Centre for Population Genomics Murdoch Children's Research Institute  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7300-1157","authenticated-orcid":false,"given":"Andre L. 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