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Autosomal dominant or recessive pathogenic variants in <jats:italic>MYH2<\/jats:italic> lead to congenital myopathy clinically featured by ophthalmoparesis and predominantly proximal weakness. <jats:italic>MYH2<\/jats:italic>-myopathy is pathologically characterized by loss and atrophy of type 2A fibers. Additional myopathological abnormalities have included rimmed vacuoles containing small p62 positive inclusions, 15\u201320\u00a0nm tubulofilaments, minicores and dystrophic changes. We report an adult patient with late-pediatric onset <jats:italic>MYH2<\/jats:italic>-myopathy caused by two heterozygous pathogenic variants: c.3331C&gt;T, p.Gln1111* predicted to result in truncation of the proximal tail region of MyHC-IIA, and c.1546T&gt;G, p.Phe516Val, affecting a highly conserved amino acid within the highly conserved catalytic motor head relay loop. This missense variant is predicted to result in a less compact loop domain and in turn could affect the protein affinity state. The patient\u2019s genotype is accompanied by a novel myopathological phenotype characterized by centralized large myofilamentous tangles associated with clusters of nemaline rods, and ring fibers, in addition to the previously reported rimmed vacuoles, paucity and atrophy of type 2A fibers. Electron microscopy demonstrated wide areas of disorganized myofibrils which were oriented in various planes of direction and entrapped multiple nemaline rods, as corresponding to the large tangles with rods seen on light microscopy. Nemaline rods were rarely observed also in nuclei. We speculate that the mutated MyHC-IIA may influence myofibril disorganization. While nemaline rods have been described in myopathies caused by pathogenic variants in genes encoding several sarcomeric proteins, to our knowledge, nemaline rods have not been previously described in <jats:italic>MYH2<\/jats:italic>-myopathy.<\/jats:p>","DOI":"10.1186\/s40478-021-01168-9","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T07:03:22Z","timestamp":1619679802000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Filamentous tangles with nemaline rods in MYH2 myopathy: a novel phenotype"],"prefix":"10.1186","volume":"9","author":[{"given":"Nicolas N.","family":"Madigan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Polzin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaofeng","family":"Cui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teerin","family":"Liewluck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad H.","family":"Alsharabati","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher J.","family":"Klein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony J.","family":"Windebank","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georges","family":"Mer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margherita","family":"Milone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,4,29]]},"reference":[{"key":"1168_CR1","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1111\/cge.12552","volume":"88","author":"M Cabrera-Serrano","year":"2015","unstructured":"Cabrera-Serrano M, Fabian VA, Boutilier J, Wise C, Faiz F, Lamont PJ et al (2015) Adult onset distal and proximal myopathy with complete ophthalmoplegia associated with a novel de novo p. 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