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Multiple mutations in <jats:italic>FLNC<\/jats:italic> are associated with myofibrillar myopathies of autosomal\u2010dominant inheritance. Here, we describe for the first time a boy with congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development but no cardiac involvement associated with a homozygous <jats:italic>FLNC<\/jats:italic> mutation c.1325C&gt;G (p.Pro442Arg). We performed ultramorphological, proteomic, and functional investigations as well as immunological studies of known marker proteins for dominant filaminopathies. We show that the mutant protein is expressed in similar quantities as the wild\u2010type variant in control skeletal muscle fibers. The proteomic signature of quadriceps muscle is altered and ultrastructural perturbations are evident. Moreover, filaminopathy marker proteins are comparable both in our homozygous and a dominant control case (c.5161delG). Biochemical investigations demonstrate that the recombinant mutant protein is less stable and more prone to degradation by proteolytic enzymes than the wild\u2010type variant. The unusual congenital presentation of the disease clearly demonstrates that homozygosity for mutations in <jats:italic>FLNC<\/jats:italic> severely aggravates the phenotype.<\/jats:p>","DOI":"10.1002\/humu.24062","type":"journal-article","created":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T17:28:41Z","timestamp":1591723721000},"page":"1600-1614","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["First clinical and myopathological description of a myofibrillar myopathy with congenital onset and homozygous mutation in <i>FLNC<\/i>"],"prefix":"10.1155","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9629-7053","authenticated-orcid":false,"given":"Heike","family":"K\u00f6lbel","sequence":"first","affiliation":[{"name":"Department of Pediatric Neurology, Developmental Neurology and Social Pediatrics Children's Hospital University of Essen Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Roos","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Developmental Neurology and Social Pediatrics Children's Hospital University of Essen Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9750-8913","authenticated-orcid":false,"given":"Peter F. 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Dortmund Germany"},{"name":"Department of Chemistry, College of Physical Sciences University of Aberdeen Aberdeen Scotland UK"},{"name":"Medizinische Proteom\u2010Center (MPC), Medizinische Fakult\u00e4t Ruhr\u2010Universit\u00e4t Bochum Bochum Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Straub","sequence":"additional","affiliation":[{"name":"The John Walton Muscular Dystrophy Research Centre, Institute of Translational and Clinical Research Newcastle University Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laxmikanth","family":"Kollipara","sequence":"additional","affiliation":[{"name":"Department of Bioanalytics Leibniz\u2010Institut f\u00fcr Analytische Wissenschaften\u2014ISAS\u2014e.V. 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