{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T14:31:06Z","timestamp":1792765866813,"version":"4.5.0"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T00:00:00Z","timestamp":1749513600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T00:00:00Z","timestamp":1749513600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pediatr Res"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Neuromuscular disorders (NMDs), rare diseases affecting the peripheral nervous system, often cause progressive weakness and systemic complications. Despite advances in genetic diagnostics, data from Southeast Asia remain limited. Ancestral variation may influence mutation spectra, revealing novel alleles and phenotypic diversity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated the diagnostic yield and clinical impact of targeted gene panel testing and exome sequencing in pediatric-onset NMDs at Siriraj Hospital, Thailand (2020\u20122024). Patients with suspected genetic NMDs and negative single-gene tests underwent gene panel testing or exome sequencing. Genetic findings were classified as positive, probable, possible, or negative.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 135 patients, the overall diagnostic yield was 69.6% (94\/135). Subgroup yields were 70.7% for inherited myopathies (53\/75), 63.3% for inherited neuropathies (31\/49), 90.0% for congenital myasthenic syndromes (9\/10), and 100% for motor neuron diseases (1\/1). Excluding patients with Duchenne muscular dystrophy, the diagnostic yield of inherited myopathies was 63.2% (36\/57). Genetic diagnoses influenced clinical care in 87.2% of cases, prompting revised diagnoses, personalized treatments, enhanced surveillance, informed family planning, and accurate prognostication.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>NGS substantially enhances diagnostic accuracy and clinical management for pediatric NMDs. These findings support incorporating NGS into diagnostic workflows for suspected genetic NMDs, thereby optimizing patient care and advancing genetic insights.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Impact<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Gene panel testing and exome sequencing demonstrate an approximately 70% diagnostic yield for pediatric neuromuscular disorders, exceeding yields reported in many other hereditary diseases.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Genetic findings underscore potential differences in mutation spectra among Southeast Asian populations, which remain under-investigated relative to Western cohorts.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Clinical implementation of next-generation sequencing confers substantial benefits, including more accurate diagnoses, personalized management, and informed family planning, ultimately improving care for pediatric neuromuscular disorders.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s41390-025-04160-4","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T04:44:29Z","timestamp":1749530669000},"page":"2195-2202","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Next-generation sequencing for pediatric-onset neuromuscular disorders unresolved by conventional diagnostic methods"],"prefix":"10.1038","volume":"98","author":[{"given":"Pimchanok","family":"Kulsirichawaroj","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mongkol","family":"Chanvanichtrakool","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pish","family":"Wattanadilokchatkun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theeraphong","family":"Pho-iam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanin","family":"Limwongse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surachai","family":"Likasitwattanakul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanokwan","family":"Boonyapisit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oranee","family":"Sanmaneechai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichizo","family":"Nishino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vorasuk","family":"Shotelersuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joohyun","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Zuchner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,10]]},"reference":[{"key":"4160_CR1","doi-asserted-by":"publisher","first-page":"73","DOI":"10.3233\/JND-140045","volume":"2","author":"JC Deenen","year":"2015","unstructured":"Deenen, J. C., Horlings, C. G., Verschuuren, J. J., Verbeek, A. L. & van Engelen, B. G. The epidemiology of neuromuscular disorders: a comprehensive overview of the literature. J. Neuromuscul. Dis. 2, 73\u201385 (2015).","journal-title":"J. Neuromuscul. Dis."},{"key":"4160_CR2","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1007\/s10072-023-07210-z","volume":"45","author":"MC Pi\u00f1eros-Fern\u00e1ndez","year":"2024","unstructured":"Pi\u00f1eros-Fern\u00e1ndez, M. C., Morte, B. & Garc\u00eda-Gim\u00e9nez, J. L. Utility of exome sequencing for the diagnosis of pediatric-onset neuromuscular diseases beyond diagnostic yield: a narrative review. Neurol. Sci. 45, 1455\u20131464 (2024).","journal-title":"Neurol. Sci."},{"key":"4160_CR3","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2023.100896","volume":"25","author":"CCY Chung","year":"2023","unstructured":"Chung, C. C. Y. et al. Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare diseases across diverse populations. Genet Med. 25, 100896 (2023).","journal-title":"Genet Med."},{"key":"4160_CR4","doi-asserted-by":"publisher","first-page":"997551","DOI":"10.3389\/fneur.2022.997551","volume":"13","author":"KWP Ng","year":"2022","unstructured":"Ng, K. W. P., Chin, H. L., Chin, A. X. Y. & Goh, D. L. Using gene panels in the diagnosis of neuromuscular disorders: a mini-review. Front. Neurol. 13, 997551 (2022).","journal-title":"Front. Neurol."},{"key":"4160_CR5","doi-asserted-by":"crossref","unstructured":"Goutman, S. A., Callaghan, B. C. & Feldman, E. A 2020 Centenary Perspective on Neuromuscular Disorders. J. Neurol. Neurosurg. Psychiatry 91, 791 (2020).","DOI":"10.1136\/jnnp-2020-324327"},{"key":"4160_CR6","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405\u2013424 (2015).","journal-title":"Genet. Med."},{"key":"4160_CR7","unstructured":"National Academies of Sciences, E. & Medicine. An evidence framework for genetic testing (The National Academies Press, 2017)."},{"key":"4160_CR8","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1016\/j.nmd.2020.08.362","volume":"30","author":"N Pattrakornkul","year":"2020","unstructured":"Pattrakornkul, N. et al. Congenital myasthenic syndromes in the thai population: clinical findings and novel mutations. Neuromuscul. Disord. 30, 851\u2013858 (2020).","journal-title":"Neuromuscul. Disord."},{"key":"4160_CR9","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-28405-6","volume":"13","author":"S Summa","year":"2023","unstructured":"Summa, S. et al. Utilisation of exome sequencing for muscular disorders in thai paediatric patients: diagnostic yield and mutational spectrum. Sci. Rep. 13, 1376 (2023).","journal-title":"Sci. Rep."},{"key":"4160_CR10","doi-asserted-by":"publisher","first-page":"191","DOI":"10.3233\/JND-230174","volume":"11","author":"P Kulsirichawaroj","year":"2024","unstructured":"Kulsirichawaroj, P. et al. Gene distribution in pediatric-onset inherited peripheral neuropathy: a single tertiary center in Thailand. J. Neuromuscul. Dis. 11, 191\u2013199 (2024).","journal-title":"J. Neuromuscul. Dis."},{"key":"4160_CR11","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1136\/jmedgenet-2014-102819","volume":"52","author":"JH Chae","year":"2015","unstructured":"Chae, J. H. et al. Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders. J. Med. Genet. 52, 208\u2013216 (2015).","journal-title":"J. Med. Genet."},{"key":"4160_CR12","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1055\/s-0039-1677734","volume":"50","author":"MA Waldrop","year":"2019","unstructured":"Waldrop, M. A. et al. Diagnostic utility of whole exome sequencing in the neuromuscular clinic. Neuropediatrics 50, 96\u2013102 (2019).","journal-title":"Neuropediatrics"},{"key":"4160_CR13","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1205","volume":"8","author":"MHY Tsang","year":"2020","unstructured":"Tsang, M. H. Y. et al. Diagnostic value of whole-exome sequencing in Chinese pediatric-onset neuromuscular patients. Mol. Genet. Genom. Med. 8, e1205 (2020).","journal-title":"Mol. Genet. Genom. Med."},{"key":"4160_CR14","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/mus.27112","volume":"63","author":"I Herman","year":"2021","unstructured":"Herman, I. et al. Clinical exome sequencing in the diagnosis of pediatric neuromuscular disease. Muscle Nerve 63, 304\u2013310 (2021).","journal-title":"Muscle Nerve"},{"key":"4160_CR15","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1002\/mus.27976","volume":"68","author":"AP Meyer","year":"2023","unstructured":"Meyer, A. P. et al. Exome sequencing in the pediatric neuromuscular clinic leads to more frequent diagnosis of both neuromuscular and neurodevelopmental conditions. Muscle Nerve 68, 833\u2013840 (2023).","journal-title":"Muscle Nerve"},{"key":"4160_CR16","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1016\/j.nmd.2018.08.012","volume":"28","author":"LN Luce","year":"2018","unstructured":"Luce, L. N. et al. Small mutation screening in the dmd gene by whole exome sequencing of an argentine duchenne\/becker muscular dystrophies cohort. Neuromuscul. Disord. 28, 986\u2013995 (2018).","journal-title":"Neuromuscul. Disord."},{"key":"4160_CR17","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1007\/s12031-022-01980-5","volume":"72","author":"GR Zamani","year":"2022","unstructured":"Zamani, G. R. et al. Genetic analysis of forty mlpa-negative duchenne muscular dystrophy patients by whole-exome sequencing. J. Mol. Neurosci. 72, 1098\u20131107 (2022).","journal-title":"J. Mol. Neurosci."},{"key":"4160_CR18","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1002\/ana.24687","volume":"80","author":"GL O\u2019Grady","year":"2016","unstructured":"O\u2019Grady, G. L. et al. Diagnosis and etiology of congenital muscular dystrophy: we are halfway there. Ann. Neurol. 80, 101\u2013111 (2016).","journal-title":"Ann. Neurol."},{"key":"4160_CR19","doi-asserted-by":"publisher","first-page":"315","DOI":"10.3233\/JND-170231","volume":"4","author":"K Vill","year":"2017","unstructured":"Vill, K. et al. Early-onset myopathies: clinical findings, prevalence of subgroups and diagnostic approach in a single neuromuscular referral center in Germany. J. Neuromuscul. Dis. 4, 315\u2013325 (2017).","journal-title":"J. Neuromuscul. Dis."},{"key":"4160_CR20","doi-asserted-by":"publisher","first-page":"107271","DOI":"10.1016\/j.clineuro.2022.107271","volume":"217","author":"AT Masri","year":"2022","unstructured":"Masri, A. T., Oweis, L., Qudah, A. A. & El-Shanti, H. Congenital muscle dystrophies: role of singleton whole exome sequencing in countries with limited resources. Clin. Neurol. Neurosurg. 217, 107271 (2022).","journal-title":"Clin. Neurol. Neurosurg."},{"key":"4160_CR21","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.nmd.2019.10.009","volume":"30","author":"SH Chan","year":"2020","unstructured":"Chan, S. H. et al. Megaconial congenital muscular dystrophy: same novel homozygous mutation in Chkb gene in two unrelated Chinese patients. Neuromuscul. Disord. 30, 47\u201353 (2020).","journal-title":"Neuromuscul. Disord."},{"key":"4160_CR22","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1136\/jnnp-2014-308826","volume":"86","author":"V Fridman","year":"2015","unstructured":"Fridman, V. et al. Cmt subtypes and disease burden in patients enrolled in the inherited neuropathies consortium natural history study: a cross-sectional analysis. J. Neurol. Neurosurg. Psychiatry 86, 873\u2013878 (2015).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"4160_CR23","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1001\/jamaneurol.2016.0171","volume":"73","author":"KM Cornett","year":"2016","unstructured":"Cornett, K. M. et al. Phenotypic variability of childhood Charcot-Marie-tooth disease. JAMA Neurol. 73, 645\u2013651 (2016).","journal-title":"JAMA Neurol."},{"key":"4160_CR24","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1016\/j.arcped.2018.09.006","volume":"25","author":"C Hoebeke","year":"2018","unstructured":"Hoebeke, C. et al. Retrospective study of 75 children with peripheral inherited neuropathy: genotype-phenotype correlations. Arch. Pediatr. 25, 452\u2013458 (2018).","journal-title":"Arch. Pediatr."},{"key":"4160_CR25","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.1002\/acn3.50797","volume":"6","author":"YH Hsu","year":"2019","unstructured":"Hsu, Y. H. et al. Mutation spectrum of Charcot-Marie-tooth disease among the Han Chinese in Taiwan. Ann. Clin. Transl. Neurol. 6, 1090\u20131101 (2019).","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"4160_CR26","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1002\/acn3.51432","volume":"8","author":"H Argente-Escrig","year":"2021","unstructured":"Argente-Escrig, H. et al. Pediatric inherited peripheral neuropathy: a prospective study at a Spanish referral center. Ann. Clin. Transl. Neurol. 8, 1809\u20131816 (2021).","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"4160_CR27","doi-asserted-by":"publisher","first-page":"100947","DOI":"10.1016\/j.gim.2023.100947","volume":"25","author":"HL Rehm","year":"2023","unstructured":"Rehm, H. L. et al. The landscape of reported vus in multi-gene panel and genomic testing: time for a change. Genet. Med. 25, 100947 (2023).","journal-title":"Genet. Med."},{"key":"4160_CR28","unstructured":"Abicht, A., M\u00fcller, J. S. & Lochm\u00fcller, H. Congenital Myasthenic Syndromes. GeneReviews [Internet]. University of Washington, Seattle; 1993\u20132025."},{"key":"4160_CR29","doi-asserted-by":"publisher","first-page":"3849","DOI":"10.1093\/brain\/awae124","volume":"147","author":"J Theuriet","year":"2024","unstructured":"Theuriet, J. et al. Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis. Brain 147, 3849\u20133862 (2024).","journal-title":"Brain"},{"key":"4160_CR30","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1002\/acn3.51346","volume":"8","author":"Y Zhao","year":"2021","unstructured":"Zhao, Y. et al. Congenital myasthenic syndrome in China: genetic and myopathological characterization. Ann. Clin. Transl. Neurol. 8, 898\u2013907 (2021).","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"4160_CR31","doi-asserted-by":"publisher","first-page":"e243","DOI":"10.1111\/j.1469-8749.2010.03663.x","volume":"52","author":"WL Yeung","year":"2010","unstructured":"Yeung, W. L., Lam, C. W. & Ng, P. C. Intra-familial variation in clinical manifestations and response to ephedrine in siblings with congenital myasthenic syndrome caused by novel COLQ mutations. Dev. Med. Child Neurol. 52, e243\u2013e244 (2010).","journal-title":"Dev. Med. Child Neurol."},{"key":"4160_CR32","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.679342","volume":"9","author":"X Luo","year":"2021","unstructured":"Luo, X. et al. Mechanisms of congenital myasthenia caused by three mutations in the COLQ gene. Front. Pediatr. 9, 679342 (2021).","journal-title":"Front. Pediatr."},{"key":"4160_CR33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2020.117260","volume":"420","author":"D Eratne","year":"2021","unstructured":"Eratne, D. et al. The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective. J. Neurol. Sci. 420, 117260 (2021).","journal-title":"J. Neurol. Sci."},{"key":"4160_CR34","unstructured":"Mona, S. et al. The landscape of peripheral neuropathy genetics: when common causes are not actually the cause. BMJ Neurology Open 4, null (2024)."},{"key":"4160_CR35","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-022-02358-x","volume":"17","author":"A Bauskis","year":"2022","unstructured":"Bauskis, A., Strange, C., Molster, C. & Fisher, C. The diagnostic Odyssey: insights from parents of children living with an undiagnosed condition. Orphanet J. Rare Dis. 17, 233 (2022).","journal-title":"Orphanet J. Rare Dis."},{"key":"4160_CR36","doi-asserted-by":"publisher","DOI":"10.1038\/s41525-017-0006-7","volume":"2","author":"D Schofield","year":"2017","unstructured":"Schofield, D. et al. Cost-effectiveness of massively parallel sequencing for diagnosis of paediatric muscle diseases. npj Genom. Med. 2, 4 (2017).","journal-title":"npj Genom. Med."}],"container-title":["Pediatric Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41390-025-04160-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41390-025-04160-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41390-025-04160-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T08:36:52Z","timestamp":1768552612000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41390-025-04160-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,10]]},"references-count":36,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["4160"],"URL":"https:\/\/doi.org\/10.1038\/s41390-025-04160-4","relation":{},"ISSN":["0031-3998","1530-0447"],"issn-type":[{"value":"0031-3998","type":"print"},{"value":"1530-0447","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,10]]},"assertion":[{"value":"14 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 May 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Informed consent or assent was obtained from participants and\/or their parent(s) or legal guardian(s) before study enrolment.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}