{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T16:49:42Z","timestamp":1775666982459,"version":"3.50.1"},"posted":{"date-parts":[[2026,4,6]]},"group-title":"Genetic and Genomic Medicine","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T00:00:00Z","timestamp":1775433600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>\n                    <jats:italic>DNM1<\/jats:italic>\n                    -related disorder is a rare developmental and epileptic encephalopathy. The current understanding of the clinical spectrum is based on sparse patient descriptions. Here, we compile the largest\n                    <jats:italic>DNM1<\/jats:italic>\n                    cohort to date, to characterize the genotypic and phenotypic landscape of the disorder.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Phenotypic data was manually curated from 95 individuals from multiple sources and harmonized using the Human Phenotype Ontology framework.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Disease-causing variants in\n                    <jats:italic>DNM1<\/jats:italic>\n                    cluster in mutational hotspots within the gene, which achieve \u2018Strong\u2019 and \u2018Moderate\u2019 evidence for pathogenicity based on ACMG guidelines. The overall\n                    <jats:italic>DNM1<\/jats:italic>\n                    phenotype was homogeneous compared to other genetic epilepsy conditions:\n                    <jats:italic>SCN2A, SCN8A, STXBP1<\/jats:italic>\n                    , and\n                    <jats:italic>SYNGAP1<\/jats:italic>\n                    . The p.R237W (n=15) variant was associated with bilateral tonic-clonic seizures, infantile spasms, and dystonia. The p.I398_R399insCR (n=14) variant was associated with severe hypotonia, profound global delay, and cortical visual impairment. Five individuals with homozygous loss-of-function variants were clinically similar to dominant-negative\n                    <jats:italic>DNM1<\/jats:italic>\n                    -related disorder, but microcephaly and brain MRI abnormalities were more common in this group.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    A harmonized cohort of individuals with\n                    <jats:italic>DNM1<\/jats:italic>\n                    -related disorder was analyzed to define mutational hotspots and reveal novel genotype-phenotype correlations. Due to the homogeneous phenotype, disease mechanism, and high proportion of recurrent variants,\n                    <jats:italic>DNM1<\/jats:italic>\n                    represents an attractive target for targeted therapy development.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.05.26350183","type":"posted-content","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T20:50:17Z","timestamp":1775508617000},"source":"Crossref","is-referenced-by-count":0,"title":["DNM1-related disorder is characterized by recurrent variants and phenotypic homogeneity"],"prefix":"10.64898","author":[{"given":"Alicia G.","family":"Harrison","sequence":"first","affiliation":[{"name":"Division of Neurology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19104, USA"},{"name":"The Epilepsy NeuroGenetics Initiative (ENGIN), Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19104, USA"},{"name":"Center for Epilepsy and NeuroDevelopmental Disorders (ENDD), CHOP\/Penn, Philadelphia, PA, 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiva","family":"Ganesan","sequence":"additional","affiliation":[{"name":"The Epilepsy NeuroGenetics Initiative (ENGIN), Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19104, USA"},{"name":"Department of Biomedical and Health Informatics (DBHi), Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19146, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongbo M.","family":"Xie","sequence":"additional","affiliation":[{"name":"The Epilepsy NeuroGenetics Initiative (ENGIN), Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19104, USA"},{"name":"Department of Biomedical and Health Informatics (DBHi), Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19146, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shridhar","family":"Parthasarathy","sequence":"additional","affiliation":[{"name":"The Epilepsy NeuroGenetics Initiative (ENGIN), Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19104, USA"},{"name":"Department of Biomedical and Health Informatics (DBHi), Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19146, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9724-0403","authenticated-orcid":false,"given":"Jillian L.","family":"McKee","sequence":"additional","affiliation":[{"name":"Division of Neurology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19104, USA"},{"name":"The Epilepsy NeuroGenetics Initiative (ENGIN), Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19104, USA"},{"name":"Department of Biomedical and Health Informatics (DBHi), Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19146, USA"},{"name":"Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA"},{"name":"Center for Epilepsy and NeuroDevelopmental Disorders (ENDD), CHOP\/Penn, Philadelphia, PA, 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan H.","family":"Magielski","sequence":"additional","affiliation":[{"name":"The Epilepsy NeuroGenetics Initiative (ENGIN), Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19104, USA"},{"name":"Department of Biomedical and Health Informatics (DBHi), Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19146, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim","family":"Thalwitzer","sequence":"additional","affiliation":[{"name":"The Epilepsy NeuroGenetics Initiative (ENGIN), Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19104, USA"},{"name":"Department of Biomedical and Health Informatics (DBHi), Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19146, 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