{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T21:16:25Z","timestamp":1792617385774,"version":"4.5.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T00:00:00Z","timestamp":1667347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100011025","name":"Government of Western Australia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015539","name":"Australian Government","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015539","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Pawsey Supercomputing Centre"},{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"publisher","award":["APP2002640"],"award-info":[{"award-number":["APP2002640"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Australian NHMRC","award":["APP1117510"],"award-info":[{"award-number":["APP1117510"]}]},{"name":"Australian NHMRC","award":["APP2007769"],"award-info":[{"award-number":["APP2007769"]}]},{"name":"Australian Government Research Training Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Nemaline myopathy 8 (NEM8) is typically a severe autosomal recessive disorder associated with variants in the kelch-like family member 40 gene (KLHL40). Common features include fetal akinesia, fractures, contractures, dysphagia, respiratory failure and neonatal death. Here, we describe a 26-year-old man with relatively mild NEM8. He presented with hypotonia and bilateral femur fractures at birth, later developing bilateral Achilles\u2019 contractures, scoliosis, and elbow and knee contractures. He had walking difficulties throughout childhood and became wheelchair bound from age 13 after prolonged immobilization. Muscle magnetic resonance imaging at age 13 indicated prominent fat replacement in his pelvic girdle, posterior compartments of thighs and vastus intermedius. Muscle biopsy revealed nemaline bodies and intranuclear rods. RNA sequencing and western blotting of patient skeletal muscle indicated significant reduction in KLHL40 mRNA and protein, respectively. Using gene panel screening, exome sequencing and RNA sequencing, we identified compound heterozygous variants in KLHL40; a truncating 10.9\u00a0kb deletion in trans with a likely pathogenic variant (c.*152G\u2009&amp;gt;\u2009T) in the 3\u2032 untranslated region (UTR). Computational tools SpliceAI and Introme predicted the c.*152G\u2009&amp;gt;\u2009T variant created a cryptic donor splice site. RNA-seq and in vitro analyses indicated that the c.*152G\u2009&amp;gt;\u2009T variant induces multiple de novo splicing events that likely provoke nonsense mediated decay of KLHL40 mRNA explaining the loss of mRNA expression and protein abundance in the patient. Analysis of 3\u2019 UTR variants in ClinVar suggests variants that introduce aberrant 3\u2019 UTR splicing may be underrecognized in Mendelian disease. We encourage consideration of this mechanism during variant curation.<\/jats:p>","DOI":"10.1093\/hmg\/ddac272","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T12:53:06Z","timestamp":1667393586000},"page":"1127-1136","source":"Crossref","is-referenced-by-count":17,"title":["A\n                    <i>KLHL40<\/i>\n                    3\u2019 UTR splice-altering variant causes milder NEM8, an under-appreciated disease mechanism"],"prefix":"10.1093","volume":"32","author":[{"given":"Lein N H","family":"Dofash","sequence":"first","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia , Nedlands, WA 6009 , Australia"},{"name":"School\u00a0of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University , Bentley, WA 6102 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin V","family":"Monahan","sequence":"additional","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia , Nedlands, WA 6009 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Servi\u00e1n-Morilla","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Roc\u00edo\/Consejo Superior de Investigaciones Cient\u00edficas\/Universidad de Sevilla , Sevilla 41013 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eloy","family":"Rivas","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital Universitario Virgen del Roc\u00edo Sevilla , Sevilla 41013 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fathimath","family":"Faiz","sequence":"additional","affiliation":[{"name":"Diagnostic Genomics , PathWest, Nedlands, WA 6009 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney , Kensington, NSW 2052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Oates","sequence":"additional","affiliation":[{"name":"School of Biotechnology & Biomolecular Sciences, The University of New South Wales , Sydney, NSW 2033 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Clayton","sequence":"additional","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia , Nedlands, WA 6009 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhonda L","family":"Taylor","sequence":"additional","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia , Nedlands, WA 6009 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R","family":"Davis","sequence":"additional","affiliation":[{"name":"Diagnostic Genomics, PathWest , Nedlands, WA 6009 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Traude","family":"Beilharz","sequence":"additional","affiliation":[{"name":"Development and Stem Cells Program, Department of Biochemistry & Molecular Biology, Biomedicine Discovery Institute, Monash University , Clayton 3800 Victoria , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel G","family":"Laing","sequence":"additional","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia , Nedlands, WA 6009 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3109-6095","authenticated-orcid":false,"given":"Macarena","family":"Cabrera-Serrano","sequence":"additional","affiliation":[{"name":"Department of Neurology, Neuromuscular Unit and Instituto de Biomedicina de Sevilla\/CSIC, Hospital Universitario Virgen del\u00a0Roc\u00edo , Sevilla 41013 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3634-211X","authenticated-orcid":false,"given":"Gianina","family":"Ravenscroft","sequence":"additional","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia , Nedlands, WA 6009 , Australia"},{"name":"School of Biomedical Sciences, University of Western Australia , Nedlands, WA 6009 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,2]]},"reference":[{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/ejhg.2012.70","article-title":"Clinical utility gene card for: nemaline myopathy","volume":"20","author":"Nowak","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/B978-0-444-64076-5.00036-3","article-title":"The genetics of congenital myopathies","volume":"148","author":"Gonorazky","year":"2018","journal-title":"Handb. Clin. Neurol."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1016\/j.nmd.2021.11.004","article-title":"The 2022 version of the gene table of neuromuscular disorders (nuclear genome)","volume":"31","author":"Cohen","year":"2021","journal-title":"Neuromuscul. Disord."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/acn3.51002","article-title":"Targeted gene panel use in 2249 neuromuscular patients: the Australasian referral center experience","volume":"7","author":"Beecroft","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s13073-022-01073-3","article-title":"Recommendations for clinical interpretation of variants found in non-coding regions of the genome","volume":"14","author":"Ellingford","year":"2022","journal-title":"Genome Med."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.ajhg.2013.05.004","article-title":"Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy","volume":"93","author":"Ravenscroft","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1002\/pd.4949","article-title":"Identification of KLHL40 mutations by targeted next-generation sequencing facilitated a prenatal diagnosis in a family with three consecutive affected fetuses with fetal akinesia deformation sequence","volume":"36","author":"Chen","year":"2016","journal-title":"Prenat. Diagn."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1016\/j.nmd.2016.07.011","article-title":"Mild clinical presentation in KLHL40-related nemaline myopathy (NEM 8)","volume":"26","author":"Seferian","year":"2016","journal-title":"Neuromuscul. Disord."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00415-015-8015-x","article-title":"KLHL40-related nemaline myopathy with a sustained, positive response to treatment with acetylcholinesterase inhibitors","volume":"263","author":"Natera-de Benito","year":"2016","journal-title":"J. Neurol."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"3529","DOI":"10.1172\/JCI74994","article-title":"KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy","volume":"124","author":"Garg","year":"2014","journal-title":"J. Clin. Invest."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"15350","DOI":"10.1074\/jbc.M114.629956","article-title":"Kelch repeat and BTB domain containing protein 5 (Kbtbd5) regulates skeletal muscle myogenesis through the E2F1-DP1 complex","volume":"290","author":"Gong","year":"2015","journal-title":"J. Biol. Chem."},{"key":"2023032011060504200_","first-page":"698","article-title":"seqr: a web-based analysis and collaboration tool for rare disease genomics","volume":"43","author":"Pais","year":"2022","journal-title":"Hum. Mutat."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting splicing from primary sequence with deep learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"S144","DOI":"10.1016\/j.nmd.2020.08.330","article-title":"P.334 introme identifies non-canonical splice-altering variants in neuromuscular patients resulting in multiple new genetic diagnoses","volume":"30","author":"Sullivan","year":"2020","journal-title":"Neuromuscul. 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Genet. Metab."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/s13023-015-0364-0","article-title":"Next generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birth","volume":"10","author":"Todd","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1002\/bies.201200073","article-title":"Introns in UTRs: why we should stop ignoring them","volume":"34","author":"Bicknell","year":"2012","journal-title":"BioEssays"},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/S0968-0004(98)01208-0","article-title":"A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance","volume":"23","author":"Nagy","year":"1998","journal-title":"Trends Biochem. Sci."},{"key":"2023032011060504200_","article-title":"Emerging roles of RNA 3\u2032-end cleavage and polyadenylation in pathogenesis, diagnosis and therapy of human disorders","volume":"10","author":"Nourse","year":"2020","journal-title":"Biomol. Ther."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1038\/s10038-018-0502-3","article-title":"Novel missense and 3'-UTR splice site variants in LHFPL5 cause autosomal recessive nonsyndromic hearing impairment","volume":"63","author":"Liaqat","year":"2018","journal-title":"J. Hum. Genet."},{"key":"2023032011060504200_","doi-asserted-by":"crossref","first-page":"3418","DOI":"10.1093\/hmg\/ddv090","article-title":"A 3'-UTR mutation creates a microRNA target site in the GFPT1 gene of patients with congenital myasthenic syndrome","volume":"24","author":"Dusl","year":"2015","journal-title":"Hum. Mol. 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Methods"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddac272\/47816788\/ddac272.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/7\/1127\/49561967\/ddac272.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/7\/1127\/49561967\/ddac272.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,6]],"date-time":"2024-10-06T19:40:37Z","timestamp":1728243637000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/32\/7\/1127\/6794016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,2]]},"references-count":50,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,11,2]]},"published-print":{"date-parts":[[2023,3,20]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddac272","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.08.08.22278402","asserted-by":"object"}]},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,4,1]]},"published":{"date-parts":[[2022,11,2]]}}}