{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T21:07:21Z","timestamp":1776287241790,"version":"3.50.1"},"reference-count":76,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T00:00:00Z","timestamp":1728604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rare diseases are heterogeneous diseases characterized by various symptoms and signs. Due to the low prevalence of such conditions (less than 1 in 2000 people), medical expertise is limited, knowledge is poor and patients\u2019 care provided by medical centers is inadequate. An accurate diagnosis is frequently challenging and ongoing research is also insufficient, thus complicating the understanding of the natural progression of the rarest disorders. This review aims at presenting the multimodal approach supported by the integration of multiple analyses and disciplines as a valuable solution to clarify complex genotype\u2013phenotype correlations and promote an in-depth examination of rare disorders. Taking into account the literature from large-scale population studies and ongoing technological advancement, this review described some examples to show how a multi-skilled team can improve the complex diagnosis of rare diseases. In this regard, Facio-Scapulo-Humeral muscular Dystrophy (FSHD) represents a valuable example where a multimodal approach is essential for a more accurate and precise diagnosis, as well as for enhancing the management of patients and their families. Given their heterogeneity and complexity, rare diseases call for a distinctive multidisciplinary approach to enable diagnosis and clinical follow-up.<\/jats:p>","DOI":"10.3390\/ijms252010949","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T08:10:16Z","timestamp":1728634216000},"page":"10949","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Deciphering the Complexity of FSHD: A Multimodal Approach as a Model for Rare Disorders"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9517-0165","authenticated-orcid":false,"given":"Domenica","family":"Megalizzi","sequence":"first","affiliation":[{"name":"Genomic Medicine Laboratory UILDM, IRCCS Fondazione Santa Lucia, Via Ardeatina 306-354, 00179 Rome, Italy"},{"name":"Department of Biomedicine and Prevention, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5056-5099","authenticated-orcid":false,"given":"Giulia","family":"Trastulli","sequence":"additional","affiliation":[{"name":"Genomic Medicine Laboratory UILDM, IRCCS Fondazione Santa Lucia, Via Ardeatina 306-354, 00179 Rome, Italy"},{"name":"Department of System Medicine, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Colantoni","sequence":"additional","affiliation":[{"name":"Genomic Medicine Laboratory UILDM, IRCCS Fondazione Santa Lucia, Via Ardeatina 306-354, 00179 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Proietti Piorgo","sequence":"additional","affiliation":[{"name":"Genomic Medicine Laboratory UILDM, IRCCS Fondazione Santa Lucia, Via Ardeatina 306-354, 00179 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7616-7008","authenticated-orcid":false,"given":"Guido","family":"Primiano","sequence":"additional","affiliation":[{"name":"Neurophysiopathology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Sancricca","sequence":"additional","affiliation":[{"name":"Neurophysiopathology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Caltagirone","sequence":"additional","affiliation":[{"name":"Department of Clinical and Behavioral Neurology, IRCCS Fondazione Santa Lucia, Via Ardeatina 306-354, 00179 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaella","family":"Cascella","sequence":"additional","affiliation":[{"name":"Genomic Medicine Laboratory UILDM, IRCCS Fondazione Santa Lucia, Via Ardeatina 306-354, 00179 Rome, Italy"},{"name":"Department of Chemical-Toxicological and Pharmacological Evaluation of Drugs, Catholic University Our Lady of Good Counsel, 1000 Tirana, Albania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1334-0920","authenticated-orcid":false,"given":"Claudia","family":"Strafella","sequence":"additional","affiliation":[{"name":"Genomic Medicine Laboratory UILDM, IRCCS Fondazione Santa Lucia, Via Ardeatina 306-354, 00179 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emiliano","family":"Giardina","sequence":"additional","affiliation":[{"name":"Genomic Medicine Laboratory UILDM, IRCCS Fondazione Santa Lucia, Via Ardeatina 306-354, 00179 Rome, Italy"},{"name":"Department of Biomedicine and Prevention, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41572-024-00505-1","article-title":"Rare Diseases: Challenges and Opportunities for Research and Public Health","volume":"10","author":"Taruscio","year":"2024","journal-title":"Nat. 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