{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:45:41Z","timestamp":1791049541132,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background and Objectives: Limb\u2013girdle muscular dystrophies (LGMDs) are a group of muscular dystrophies characterized by predominantly proximal-muscle weakness, with a highly heterogeneous genetic etiology. Despite recent efforts, the epidemiology of LGMDs is still under-evaluated. However, a better understanding of the distribution and genetic characteristics of LGMDs is required to optimize the diagnostic process and to address future research. Therefore, the aim of the present study is to investigate and identify new pathogenic variants, to better characterize LGMDs in Sicily. Methods: We enrolled patients with genetic and clinical diagnosis of LGMD referred to our clinic between the years 2019 and 2025. A targeted next-generation-sequencing (NGS) panel was performed, based on the reported disease frequency. A retrospective analysis of the clinical, laboratory, electrophysiological, and histological features was performed. Results: A total of 28 LGMDs patients aged 56.6 years (47.2\u201360.5 IQR) were identified (16 males, 57%). A molecular diagnosis was achieved in 24 (85.7%) of patients, most commonly carrying mutations in CAPN3 (14 patients, 50%), followed by DYSF, LAMA2, ANO5, FKTN and TTN genes. Pathogenic variants in CAPN3 and LAMA2 were associated with earlier onset and longer disease duration, whereas ANO5 presented later with a milder course. Cardiac involvement was observed more frequently in patients with LAMA2 and FKTN mutations. Association between heterozygous mutations in the CAPN3 and DYSF, as well as between CAPN3 and DMD variants were reported. Discussion: The findings of this study provide valuable insights into the epidemiology of LGMDs in the Western Sicily, offering important contributions to genotype\u2013phenotype correlations. Our analysis highlights the role of genetic diagnosis in achieving accurate classification of the disease and optimizing clinical management.<\/jats:p>","DOI":"10.3390\/genes16080987","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T12:31:26Z","timestamp":1755865886000},"page":"987","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Genetic and Clinical Spectrum of Limb\u2013Girdle Muscular Dystrophies in Western Sicily"],"prefix":"10.3390","volume":"16","author":[{"given":"Nicasio","family":"Rini","sequence":"first","affiliation":[{"name":"Department of Biomedicine, Neuroscience, and Advanced Diagnostic (BIND), University of Palermo, 90129 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1499-9460","authenticated-orcid":false,"given":"Antonino","family":"Lupica","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience, and Advanced Diagnostic (BIND), University of Palermo, 90129 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3627-8974","authenticated-orcid":false,"given":"Paolo","family":"Alonge","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience, and Advanced Diagnostic (BIND), University of Palermo, 90129 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4830-9544","authenticated-orcid":false,"given":"Grazia","family":"Crescimanno","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience, and Advanced Diagnostic (BIND), University of Palermo, 90129 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8883-5701","authenticated-orcid":false,"given":"Antonia","family":"Pignolo","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience, and Advanced Diagnostic (BIND), University of Palermo, 90129 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3027-7863","authenticated-orcid":false,"given":"Christian","family":"Messina","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience, and Advanced Diagnostic (BIND), University of Palermo, 90129 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3310-782X","authenticated-orcid":false,"given":"Sandro","family":"Santa Paola","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5083-1174","authenticated-orcid":false,"given":"Marika","family":"Giuliano","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5458-7415","authenticated-orcid":false,"given":"Eugenia","family":"Borgione","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5961-0362","authenticated-orcid":false,"given":"Mariangela","family":"Lo Giudice","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5901-0041","authenticated-orcid":false,"given":"Carmela","family":"Scuderi","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9805-1655","authenticated-orcid":false,"given":"Vincenzo","family":"Di Stefano","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience, and Advanced Diagnostic (BIND), University of Palermo, 90129 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5875-3126","authenticated-orcid":false,"given":"Filippo","family":"Brighina","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience, and Advanced Diagnostic (BIND), University of Palermo, 90129 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/S0140-6736(12)61897-2","article-title":"Muscular Dystrophies","volume":"381","author":"Mercuri","year":"2013","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.nmd.2018.05.007","article-title":"229th ENMC international workshop: Limb girdle muscular dystrophies\u2014Nomenclature and reformed classification Naarden, the Netherlands, 17\u201319 March 2017","volume":"28","author":"Straub","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.3233\/JND-150105","article-title":"The Classification, Natural History and Treatment of the Limb Girdle Muscular Dystrophies","volume":"2","author":"Murphy","year":"2015","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1080\/14737175.2018.1508997","article-title":"An update on diagnostic options and considerations in limb-girdle dystrophies","volume":"18","author":"Angelini","year":"2018","journal-title":"Expert Rev. Neurother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1212\/WNL.0000000000000892","article-title":"Evidence-based guideline summary: Diagnosis and treatment of limb-girdle and distal dystrophies: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine","volume":"83","author":"Narayanaswami","year":"2014","journal-title":"Neurology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1093\/brain\/77.2.169","article-title":"On the classification, natural history and treatment of the myopathies","volume":"77","author":"Walton","year":"1954","journal-title":"Brain"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1002\/acn3.649","article-title":"Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients","volume":"5","author":"Nallamilli","year":"2018","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"203","DOI":"10.3892\/ijmm.2021.5036","article-title":"CAPN3: A muscle-specific calpain with an important role in the pathogenesis of diseases (Review)","volume":"48","author":"Chen","year":"2021","journal-title":"Int. J. Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nature01573","article-title":"Defective membrane repair in dysferlin-deficient muscular dystrophy","volume":"423","author":"Bansal","year":"2003","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"27664","DOI":"10.1074\/jbc.271.44.27664","article-title":"Structure of the human laminin \u03b12-chain gene (LAMA2), which is affected in congenital muscular dystrophy","volume":"271","author":"Zhang","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.ajhg.2009.12.013","article-title":"Recessive Mutations in the Putative Calcium-Activated Chloride Channel Anoctamin 5 Cause Proximal LGMD2L and Distal MMD3 Muscular Dystrophies","volume":"86","author":"Bolduc","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.1093\/hmg\/10.25.2851","article-title":"Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 21 as a milder allelic variant of congenital muscular dystrophy MDC1C","volume":"10","author":"Brockington","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"293","DOI":"10.3233\/JND-160158","article-title":"Increasing Role of Titin Mutations in Neuromuscular Disorders","volume":"3","author":"Savarese","year":"2016","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_14","first-page":"1","article-title":"Genetic basis of limb-girdle muscular dystrophies: The 2014 update","volume":"33","author":"Nigro","year":"2014","journal-title":"Acta Myol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2512","DOI":"10.1038\/s41436-019-0544-8","article-title":"Estimating prevalence for limb-girdle muscular dystrophy based on public sequencing databases","volume":"21","author":"Liu","year":"2019","journal-title":"Genet. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1002\/mus.25192","article-title":"The italian limb girdle muscular dystrophy registry: Relative frequency, clinical features, and differential diagnosis","volume":"55","author":"Magri","year":"2017","journal-title":"Muscle Nerve"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1002\/ana.10559","article-title":"Phenotypic spectrum associated with mutations in the fukutin-related protein gene","volume":"53","author":"Mercuri","year":"2003","journal-title":"Ann. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.nmd.2012.05.001","article-title":"Frequency and characterisation of anoctamin 5 mutations in a cohort of Italian limb-girdle muscular dystrophy patients","volume":"22","author":"Magri","year":"2012","journal-title":"Neuromuscul. Disord."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1093\/brain\/awq294","article-title":"A founder mutation in Anoctamin 5 is a major cause of limb-girdle muscular dystrophy","volume":"134","author":"Hicks","year":"2011","journal-title":"Brain"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1093\/rheumatology\/kem211","article-title":"The predictive value of creatine kinase, EMG and MRI in diagnosing muscle disease","volume":"46","author":"Cardy","year":"2007","journal-title":"Rheumatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.21873\/invivo.11427","article-title":"Diagnostic accuracy of muscle biopsy and electromyography in 123 patients with neuromuscular disorders","volume":"32","author":"Constantinides","year":"2018","journal-title":"Vivo"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S0960-8966(96)00387-2","article-title":"Chromosome 15-linked limb-girdle muscular dystrophy: Clinical phenotypes in Reunion Island and French metropolitan communities","volume":"6","author":"Fardeau","year":"1996","journal-title":"Neuromuscul. Disord."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1093\/brain\/119.1.295","article-title":"Juvenile limb-girdle muscular dystrophy Clinical, histopathological and genetic data from a small community living in the Reunion Island","volume":"119","author":"Fardeau","year":"1996","journal-title":"Brain"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kimura, J. (2013). Electrodiagnosis in Diseases of Nerve and Muscle: Principles and Practice, Oxford University Press.","DOI":"10.1093\/med\/9780199738687.001.0001"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1111\/ene.15306","article-title":"Clinico-genetic spectrum of limb-girdle muscular weakness in Austria: A multicentre cohort study","volume":"29","author":"Krenn","year":"2022","journal-title":"Eur. J. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1055\/s-0043-1772833","article-title":"Single-centre experience with autosomal recessive limb-girdle muscular dystrophy: Case series and literature review","volume":"81","author":"Lorenzoni","year":"2023","journal-title":"Arq. Neuro-Psiquiatr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.nmd.2018.03.010","article-title":"233rd ENMC International Workshop:: Clinical Trial Readiness for Calpainopathies, Naarden, The Netherlands, 15\u201317 September 2017","volume":"28","author":"Lostal","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e89","DOI":"10.1212\/NXG.0000000000000089","article-title":"The clinical outcome study for dysferlinopathy an international multicenter study","volume":"2","author":"Harris","year":"2016","journal-title":"Neurol. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/humu.9355","article-title":"Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies","volume":"26","author":"Nguyen","year":"2005","journal-title":"Hum. Mutat."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1111\/cge.14216","article-title":"Dysferlinopathies: Clinical and genetic variability","volume":"102","author":"Ivanova","year":"2022","journal-title":"Clin. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.nmd.2010.02.001","article-title":"Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations","volume":"20","author":"Geranmayeh","year":"2010","journal-title":"Neuromuscul. Disord."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2414","DOI":"10.1007\/s00415-021-10806-0","article-title":"Diagnostic interest of whole-body MRI in early- and late-onset LAMA2 muscular dystrophies: A large international cohort","volume":"269","author":"Haberlova","year":"2022","journal-title":"J. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1002\/acn3.51042","article-title":"Global FKRP Registry: Observations in more than 300 patients with Limb Girdle Muscular Dystrophy R9","volume":"7","author":"Murphy","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1038\/s41436-020-0914-2","article-title":"Genotype\u2013phenotype correlations in recessive titinopathies","volume":"22","author":"Savarese","year":"2020","journal-title":"Genet. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.nmd.2020.09.032","article-title":"The importance of an integrated genotype-phenotype strategy to unravel the molecular bases of titinopathies","volume":"30","author":"Perrin","year":"2020","journal-title":"Neuromuscul. Disord."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1002\/acn3.50801","article-title":"Clinical and molecular findings in a cohort of ANO5-related myopathy","volume":"6","author":"Silva","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1091\/mbc.e14-04-0947","article-title":"Calpain cleavage within dysferlin exon 40a releases a synaptotagmin-like module for membrane repair","volume":"25","author":"Redpath","year":"2014","journal-title":"Mol. Biol. Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1293\/tox.25.135","article-title":"Dysferlin and animal models for dysferlinopathy","volume":"25","author":"Kobayashi","year":"2012","journal-title":"J. Toxicol. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1093\/brain\/awae358","article-title":"Natural history of Becker muscular dystrophy: DMD gene mutations predict clinical severity","volume":"148","author":"Gorgoglione","year":"2025","journal-title":"Brain"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1002\/ejhf.2284","article-title":"The heart of dystrophinopathies","volume":"23","author":"Sinagra","year":"2021","journal-title":"Eur. J. Heart Fail."},{"key":"ref_41","first-page":"1424","article-title":"Use of whole-exome sequencing for diagnosis of limb-girdle muscular dystrophy: Outcomes and lessons learned","volume":"72","author":"Ghaoui","year":"2015","journal-title":"J. Am. Med. Assoc. Neurol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/987\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:32:49Z","timestamp":1760034769000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/987"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,21]]},"references-count":41,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["genes16080987"],"URL":"https:\/\/doi.org\/10.3390\/genes16080987","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,21]]}}}