{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T21:11:00Z","timestamp":1793740260052,"version":"4.6.1"},"reference-count":58,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2018,12,1]],"date-time":"2018-12-01T00:00:00Z","timestamp":1543622400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100002160","name":"Jain Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002160","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2018,12]]},"abstract":"Abstract<\/jats:title>Objective<\/jats:title>Limb\u2010girdle muscular dystrophies (LGMD<\/jats:styled-content>s), one of the most heterogeneous neuromuscular disorders (NMD<\/jats:styled-content>s), involves predominantly proximal\u2010muscle weakness with >30 genes associated with different subtypes. The clinical\u2010genetic overlap among subtypes and with other NMD<\/jats:styled-content>s complicate disease\u2010subtype identification lengthening diagnostic process, increases overall costs hindering treatment\/clinical\u2010trial recruitment. Currently seven LGMD<\/jats:styled-content> clinical trials are active but still no gene\u2010therapy\u2010related treatment is available. Till\u2010date no nation\u2010wide large\u2010scale LGMD<\/jats:styled-content> sequencing program was performed. Our objectives were to understand LGMD<\/jats:styled-content> genetic basis, different subtypes\u2019 relative prevalence across US<\/jats:styled-content> and investigate underlying disease mechanisms.<\/jats:p><\/jats:sec>Methods<\/jats:title>A total of 4656 patients with clinically suspected\u2010LGMD<\/jats:styled-content> across US<\/jats:styled-content> were recruited to conduct next\u2010generation sequencing (NGS<\/jats:styled-content>)\u2010based gene\u2010panel testing during June\u20102015 to June\u20102017 in CLIA<\/jats:styled-content>\u2010CAP<\/jats:styled-content>\u2010certified Emory\u2010Genetics\u2010Laboratory. Thirty\u2010five LGMD<\/jats:styled-content>\u2010subtypes\u2010associated or LGMD<\/jats:styled-content>\u2010like other NMD<\/jats:styled-content>\u2010associated genes were investigated. Main outcomes were diagnostic yield, gene\u2010variant spectrum, and LGMD<\/jats:styled-content> subtypes\u2019 prevalence in a large US LGMD<\/jats:styled-content>\u2010suspected population.<\/jats:p><\/jats:sec>Results<\/jats:title>Molecular diagnosis was established in 27% (1259 cases; 95% CI<\/jats:styled-content>, 26\u201329%) of the patients with major contributing genes to LGMD<\/jats:styled-content> phenotypes being: CAPN<\/jats:styled-content>3<\/jats:italic>(17%), DYSF<\/jats:styled-content><\/jats:italic>(16%), FKRP<\/jats:styled-content><\/jats:italic>(9%) and ANO<\/jats:styled-content>5<\/jats:italic>(7%). We observed an increased prevalence of genetically confirmed late\u2010onset Pompe disease, DNAJB<\/jats:styled-content>6\u2010<\/jats:italic>associated LGMD<\/jats:styled-content> subtype1E and CAPN<\/jats:styled-content>3<\/jats:italic>\u2010associated autosomal\u2010dominant LGMD<\/jats:styled-content>s. Interestingly, we identified a high prevalence of patients with pathogenic variants in more than one LGMD<\/jats:styled-content> gene suggesting possible synergistic heterozygosity\/digenic\/multigenic contribution to disease presentation\/progression that needs consideration as a part of diagnostic modality.<\/jats:p><\/jats:sec>Interpretation<\/jats:title>Overall, this study has improved our understanding of the relative prevalence of different LGMD<\/jats:styled-content> subtypes, their respective genetic etiology, and the changing paradigm of their inheritance modes and novel mechanisms that will allow for improved timely treatment, management, and enrolment of molecularly diagnosed individuals in clinical trials.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.649","type":"journal-article","created":{"date-parts":[[2018,12,2]],"date-time":"2018-12-02T05:10:03Z","timestamp":1543727403000},"page":"1574-1587","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":176,"title":["Genetic landscape and novel disease mechanisms from a large LGMD<\/scp> cohort of 4656 patients"],"prefix":"10.1002","volume":"5","author":[{"given":"Babi Ramesh Reddy","family":"Nallamilli","sequence":"first","affiliation":[{"name":"Emory University Department of Human Genetics Atlanta Georgia 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samya","family":"Chakravorty","sequence":"additional","affiliation":[{"name":"Emory University Department of Human Genetics Atlanta Georgia 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akanchha","family":"Kesari","sequence":"additional","affiliation":[{"name":"Emory University Department of Human Genetics Atlanta Georgia 30322"},{"name":"EGL Genetics\u2010Eurofins Tucker Atlanta Georgia 30084"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Tanner","sequence":"additional","affiliation":[{"name":"Emory University Department of Human Genetics Atlanta Georgia 30322"},{"name":"EGL Genetics\u2010Eurofins Tucker Atlanta Georgia 30084"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arunkanth","family":"Ankala","sequence":"additional","affiliation":[{"name":"Emory University Department of Human Genetics Atlanta Georgia 30322"},{"name":"EGL Genetics\u2010Eurofins Tucker Atlanta Georgia 30084"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Schneider","sequence":"additional","affiliation":[{"name":"EGL Genetics\u2010Eurofins Tucker Atlanta Georgia 30084"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"da Silva","sequence":"additional","affiliation":[{"name":"EGL Genetics\u2010Eurofins Tucker Atlanta Georgia 30084"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randall","family":"Beadling","sequence":"additional","affiliation":[{"name":"EGL Genetics\u2010Eurofins Tucker Atlanta Georgia 30084"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Alexander","sequence":"additional","affiliation":[{"name":"Emory University Department of Human Genetics Atlanta Georgia 30322"},{"name":"EGL Genetics\u2010Eurofins Tucker Atlanta Georgia 30084"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Hussain","family":"Askree","sequence":"additional","affiliation":[{"name":"Emory University Department of Human Genetics Atlanta Georgia 30322"},{"name":"EGL Genetics\u2010Eurofins Tucker Atlanta Georgia 30084"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Whitt","sequence":"additional","affiliation":[{"name":"Emory University Department of Human Genetics Atlanta Georgia 30322"},{"name":"Augusta University Augusta Georgia 30912"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lora","family":"Bean","sequence":"additional","affiliation":[{"name":"Emory University Department of Human Genetics Atlanta Georgia 30322"},{"name":"EGL Genetics\u2010Eurofins Tucker Atlanta Georgia 30084"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christin","family":"Collins","sequence":"additional","affiliation":[{"name":"Emory University Department of Human Genetics Atlanta Georgia 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish","family":"Khadilkar","sequence":"additional","affiliation":[{"name":"Department of Neurology Bombay Hospital Mumbai Maharashtra India"},{"name":"Department of Neurology Sir J J Group of Hospitals Grant Medical College Mumbai Maharashtra India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradnya","family":"Gaitonde","sequence":"additional","affiliation":[{"name":"Centre for Advanced Molecular Diagnostics in Neuromuscular Disorders (CAMDND) 400022 Mumbai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashna","family":"Dastur","sequence":"additional","affiliation":[{"name":"Centre for Advanced Molecular Diagnostics in Neuromuscular Disorders (CAMDND) 400022 Mumbai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Wicklund","sequence":"additional","affiliation":[{"name":"Neurology The University of Colorado at Denver \u2010 Anschutz Medical Campus Aurora Colorado 80045"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahseen","family":"Mozaffar","sequence":"additional","affiliation":[{"name":"Neurology University of California, Irvine Orange California 92868"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Harms","sequence":"additional","affiliation":[{"name":"Department of Neurology Columbia University New York New York 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Rufibach","sequence":"additional","affiliation":[{"name":"Jain Foundation Seattle Wisconsin 98115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Plavi","family":"Mittal","sequence":"additional","affiliation":[{"name":"In\u2010Depth Genomics Bellevue Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhuri","family":"Hegde","sequence":"additional","affiliation":[{"name":"Emory University Department of Human Genetics Atlanta Georgia 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,12]]},"reference":[{"key":"e_1_2_8_2_1","first-page":"1","article-title":"Genetic basis of limb\u2010girdle muscular dystrophies: the 2014 update","volume":"33","author":"Nigro V","year":"2014","journal-title":"Acta Myol"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.25367"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.10.1875"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2014.2048"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20642"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201212142"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2014.12.009"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2015.11.012"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0b013e32834aa38d"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-8-171"},{"key":"e_1_2_8_12_1","first-page":"12","article-title":"Collaborating to bring new therapies to the patient\u2013the TREAT\u2010NMD model","volume":"28","author":"Bushby K","year":"2009","journal-title":"Acta Myol"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0175343"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002800"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2016.116"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.25192"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678707.2016.1256769"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24303"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-016-8036-0"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2015.03.011"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13031"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2016.00092"},{"key":"e_1_2_8_23_1","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1093\/ecco-jcc\/jjy068","article-title":"Diagnostic yield of next\u2010generation sequencing in very early\u2010onset inflammatory bowel diseases: a multicenter study","volume":"12","author":"Charbit\u2010Henrion F","year":"2018","journal-title":"J Crohns Colitis"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1136\/jclinpath-2017-204978"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2017-104811"},{"key":"e_1_2_8_26_1","doi-asserted-by":"crossref","first-page":"302","DOI":"10.4103\/aian.AIAN_129_17","article-title":"Detection of dysferlin gene pathogenic variants in the indian population in patients predicted to have a dysferlinopathy using a blood\u2010based monocyte assay and clinical algorithm: a model for accurate and cost\u2010effective diagnosis","volume":"20","author":"Dastur RS","year":"2017","journal-title":"Ann Indian Acad Neurol"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.spen.2012.09.008"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22364"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.24195"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22591"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029061"},{"key":"e_1_2_8_33_1","first-page":"1128","article-title":"Multiple independent molecular etiology for limb\u2010girdle muscular dystrophy type 2A patients from various geographical origins","volume":"60","author":"Richard I","year":"1997","journal-title":"Am J Hum Genet"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww133"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.25970"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl062"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2008.9"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181aae851"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2454"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.96"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.jnen.0000235854.77716.6c"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306555"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000212"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-083115-022545"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/1682"},{"key":"e_1_2_8_46_1","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1007\/s00401-002-0654-1","article-title":"Clinical, morphological and immunological evaluation of six patients with dysferlin deficiency","volume":"105","author":"Prelle A","year":"2003","journal-title":"Acta Neuropathol"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002758"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.08.005"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2018.03.011"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2004.05.005"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2006.10.001"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2014.01.014"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.24106"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.1103"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2015.07.014"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23427"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2017.276980"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aal5209"},{"key":"e_1_2_8_59_1","first-page":"1","article-title":"Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole\u2010genome sequencing as a first\u2010tier genetic test","volume":"1","author":"Lionel AC","year":"2017","journal-title":"Genet Med"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Facn3.649","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.649","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acn3.649","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.649","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T11:56:04Z","timestamp":1694778964000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.649"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12]]},"references-count":58,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2018,12]]}},"alternative-id":["10.1002\/acn3.649"],"URL":"https:\/\/doi.org\/10.1002\/acn3.649","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12]]},"assertion":[{"value":"2018-08-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-08-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-12-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}