{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:27:30Z","timestamp":1786976850131,"version":"build-2736575974"},"reference-count":31,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T00:00:00Z","timestamp":1597017600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["309548"],"award-info":[{"award-number":["309548"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007155","name":"Medical Research Council Canada","doi-asserted-by":"publisher","award":["MR\/N025431\/1"],"award-info":[{"award-number":["MR\/N025431\/1"]}],"id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["R01 HG009141"],"award-info":[{"award-number":["R01 HG009141"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010897","name":"Newton Fund","doi-asserted-by":"publisher","award":["MR\/N027302\/1"],"award-info":[{"award-number":["MR\/N027302\/1"]}],"id":[{"id":"10.13039\/100010897","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin\u20102 (\n                    <jats:italic>SYT2<\/jats:italic>\n                    ), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in\n                    <jats:italic>SYT2<\/jats:italic>\n                    have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant\u2010negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in\n                    <jats:italic>SYT2,<\/jats:italic>\n                    clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes\n                    <jats:italic>SYT2<\/jats:italic>\n                    as a CMS\u2010disease gene and expands its clinical and genetic spectrum to include recessive loss\u2010of\u2010function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.61765","type":"journal-article","created":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T03:45:54Z","timestamp":1597031154000},"page":"2272-2283","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Biallelic loss of function variants in\n                    <scp>\n                      <i>SYT2<\/i>\n                    <\/scp>\n                    cause a treatable congenital onset presynaptic myasthenic syndrome"],"prefix":"10.1002","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6399-1444","authenticated-orcid":false,"given":"Sandra","family":"Donkervoort","sequence":"first","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Payam","family":"Mohassel","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Laugwitz","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Department of Paediatric Neurology University Children's Hospital  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha S.","family":"Zaki","sequence":"additional","affiliation":[{"name":"Clinical Genetics Department, Human Genetics and Genome Research Division National Research Centre  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik\u2010Jan","family":"Kamsteeg","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Maroofian","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disorders University College London Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine R.","family":"Chao","sequence":"additional","affiliation":[{"name":"Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corien C.","family":"Verschuuren\u2010Bemelmans","sequence":"additional","affiliation":[{"name":"Department of Genetics University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronka","family":"Horber","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology University Children's Hospital  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemarie J. M.","family":"Fock","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riley M.","family":"McCarty","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minal S.","family":"Jain","sequence":"additional","affiliation":[{"name":"Rehabilitation Medicine Department, Clinical Research Center, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Biancavilla","sequence":"additional","affiliation":[{"name":"Rehabilitation Medicine Department, Clinical Research Center, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"McMacken","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Royal Victoria Hospital  Belfast UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Nalls","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicol C.","family":"Voermans","sequence":"additional","affiliation":[{"name":"Department of Neurology Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasnaa M.","family":"Elbendary","sequence":"additional","affiliation":[{"name":"Clinical Genetics Department, Human Genetics and Genome Research Division National Research Centre  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly","family":"Snyder","sequence":"additional","affiliation":[{"name":"Department of Neurology Children's Health  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyu","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Pathology UT Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya J.","family":"Lehky","sequence":"additional","affiliation":[{"name":"EMG Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Stanley","sequence":"additional","affiliation":[{"name":"Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, University of California  San Diego California USA"},{"name":"Rady Children's Institute for Genomic Medicine, Rady Children's Hospital  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan T.","family":"Iannaccone","sequence":"additional","affiliation":[{"name":"Department of Pediatrics UT Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Reghan","family":"Foley","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanns","family":"Lochm\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics and Muscle Disorders Medical Center \u2013 University of Freiburg, Faculty of Medicine  Freiburg Germany"},{"name":"Children's Hospital of Eastern Ontario Research Institute, University of Ottawa  Ottawa Ontario Canada"},{"name":"Division of Neurology, Department of Medicine The Ottawa Hospital  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Gleeson","sequence":"additional","affiliation":[{"name":"Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, University of California  San Diego California USA"},{"name":"Rady Children's Institute for Genomic Medicine, Rady Children's Hospital  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disorders University College London Institute of Neurology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias B.","family":"Haack","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Horvath","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten G.","family":"B\u00f6nnemann","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,8,10]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007319"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy209"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-8966(01)00193-6"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-04-01206.1997"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2018.07.008"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000305"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1832"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-018-0852-4"},{"issue":"5","key":"e_1_2_9_10_1","first-page":"461","article-title":"Congenital myasthenic syndromes: Pathogenesis, diagnosis, and treatment","volume":"14","author":"Engel A. 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