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These conditions are categorised according to distinctive myopathological features and causative genes. Despite advances in diagnosis through massive parallel sequencing and progress in understanding the underlying pathogenesis, many aspects of these disorders remain poorly understood. <jats:italic>MYL1<\/jats:italic>\u2010related congenital myopathy is an ultra\u2010rare and severe condition, associated with a deficiency of essential\/alkali light myosin and impaired development of fast\u2010twitch type II muscle fibres. This study aims to advance the understanding of the phenotype and pathogenesis of MYL1\u2010congenital myopathy.<\/jats:p><jats:p>We analysed the clinical characteristics of two individuals harbouring three novel variants in the <jats:italic>MYL1<\/jats:italic> gene. We conducted detailed genomic analysis and extensive studies on their muscles using histological, immunohistochemical, immunofluorescence, Western Blot and electron microscopy. Both individuals showed a very severe congenital myopathy, characterised by congenital hypotonia and weakness, requiring ventilatory and nutritional assistance. Muscle biopsy revealed dystrophic\u2010like or myopathic changes, with notable smallness of fast\u2010twitch type II fibres, often arranged around larger type I fibres, drawing a floret pattern. These fibres expressed developmental myosin and exhibited features of aberrant myofibrillogenesis. Type I myofibres exhibited correct sarcomere alignment, but like the small fast\u2010twitch fibres, both showed distorted cell organelles, vacuolar aggregates and membranous debris, indicating autophagic impairment.<\/jats:p><jats:p>Our findings confirm that bi\u2010allelic <jats:italic>MYL1<\/jats:italic> variants are associated with a severe congenital myopathy, characterised by a distinctive clinical and histopathological phenotype involving impaired type II fibre development. Additionally, our study reveals a role for MYL1 in the organisation and trophism of all muscle fibre types.<\/jats:p><\/jats:sec><jats:sec><jats:title>Summary<\/jats:title><jats:p>\n<jats:list list-type=\"bullet\">\n\n<jats:list-item><jats:p><jats:italic>MYL1<\/jats:italic> biallelic variants cause severe congenital myopathy with early hypotonia and type II fibre hypotrophy.<\/jats:p><\/jats:list-item>\n\n<jats:list-item><jats:p>Muscle biopsy shows a distinct pattern, including floret\u2010like fibre arrangement.<\/jats:p><\/jats:list-item>\n\n<jats:list-item><jats:p>Findings suggest a broader role for MYL1 in fibre organisation and autophagy across muscle fibre types.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.70025","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T12:00:24Z","timestamp":1749470424000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<i>MYL1<\/i>\u2010Related Congenital Myopathy: Clinical, Genetic and Pathological Insights"],"prefix":"10.1111","volume":"51","author":[{"given":"Irene","family":"Madrigal","sequence":"first","affiliation":[{"name":"Biochemistry and Molecular Genetics Department Hospital Clinic of Barcelona and Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS)  Barcelona Spain"},{"name":"CIBER of Rare Diseases (CIBERER) Instituto de Salud Carlos III  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Villar\u2010Vera","sequence":"additional","affiliation":[{"name":"Department of Paediatrics 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Hospital Clinic of Barcelona and Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS)  Barcelona Spain"},{"name":"CIBER of Rare Diseases (CIBERER) Instituto de Salud Carlos III  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Piolatti\u2010Luna","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Hospital Clinico Universitario de Valencia  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2349-7481","authenticated-orcid":false,"given":"Nuria","family":"Muelas","sequence":"additional","affiliation":[{"name":"CIBER of Rare Diseases (CIBERER) Instituto de Salud Carlos III  Madrid Spain"},{"name":"Neuromuscular and Ataxias Research Group Health Research Institute Hospital La Fe (IIS La Fe)  Valencia Spain"},{"name":"Neuromuscular Diseases Unit, Neurology Department Hospital Universitari i Polit\u00e8cnic La Fe  Valencia 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