{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T04:10:25Z","timestamp":1788840625113,"version":"build-2803163510"},"reference-count":16,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Protein\u2010truncating variants in the 3\u2032 region of a transcript, evading mRNA degradation and giving rise to aberrant truncated proteins, are an underrecognized cause in Mendelian diseases. Here, we report two individuals with heterozygous\n                    <jats:italic>de novo<\/jats:italic>\n                    nonsense variants in the penultimate and last exon of\n                    <jats:italic>NUSAP1<\/jats:italic>\n                    , both presenting with early\u2010onset refractory epilepsy, global developmental delay, congenital microcephaly, and a recognizable facial gestalt. RNA sequencing performed in one individual did not show a reduction in expression, compatible with escape of aberrant transcripts from nonsense mediated mRNA decay (NMD). We systematically analyzed gnomAD population data to delineate a critical region at the 3\u2032 region of\n                    <jats:italic>NUSAP1<\/jats:italic>\n                    , where nonsense variants introduce a premature termination codon and escape NMD. Such variants are absent from healthy controls, while frameshift variants producing C\u2010terminal elongations appear tolerated. This position\u2010dependent model provides guidance for diagnostic variant interpretation.\n                  <\/jats:p>","DOI":"10.1111\/cge.70244","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T03:54:53Z","timestamp":1788839693000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pathogenicity of\n                    <scp>\n                      <i>NUSAP1<\/i>\n                    <\/scp>\n                    Variants Is Defined by\n                    <scp>NMD<\/scp>\n                    \u2010Escape: Evidence From Two Novel Cases and Systematic Population\u2010Based Variant Analysis"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6735-9205","authenticated-orcid":false,"given":"Maureen","family":"Jacob","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4083-9230","authenticated-orcid":false,"given":"Susann","family":"Badmann","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0336-7097","authenticated-orcid":false,"given":"Stefania","family":"Bigoni","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Department of Mother and Child and Department of Medical Science Ferrara University Hospital and Ferrara University  Ferrara Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4707-212X","authenticated-orcid":false,"given":"Maria","family":"Iascone","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Papa Giovanni XXIII Hospital  Bergamo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Vivaldi","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Department of Mother and Child and Department of Medical Science Ferrara University Hospital and Ferrara University  Ferrara Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Mayerhanser","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9119-3455","authenticated-orcid":false,"given":"Robert","family":"Kopajtich","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich  Munich Germany"},{"name":"Institute of Neurogenomics, Helmholtz Zentrum M\u00fcnchen  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2379-6286","authenticated-orcid":false,"given":"Holger","family":"Prokisch","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich  Munich Germany"},{"name":"Institute of Neurogenomics, Helmholtz Zentrum M\u00fcnchen  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Forest","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Pediatric Section University Hospital of Ferrara  Ferrara Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Eck","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich  Munich Germany"},{"name":"Institute of Neurogenomics, Helmholtz Zentrum M\u00fcnchen  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8112-9153","authenticated-orcid":false,"given":"Michael","family":"Zech","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich  Munich Germany"},{"name":"Institute of Neurogenomics, Helmholtz Zentrum M\u00fcnchen  Munich Germany"},{"name":"Institute for Advanced Study, Technical University of Munich  Garching Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1119-2285","authenticated-orcid":false,"given":"Elisabeth","family":"Graf","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4454-8823","authenticated-orcid":false,"given":"Matias","family":"Wagner","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich  Munich Germany"},{"name":"Institute of Neurogenomics, Helmholtz Zentrum M\u00fcnchen  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3074-599X","authenticated-orcid":false,"given":"Juliane","family":"Winkelmann","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich  Munich Germany"},{"name":"Institute of Neurogenomics, Helmholtz Zentrum M\u00fcnchen  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5183-780X","authenticated-orcid":false,"given":"Theresa","family":"Brunet","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6920-8550","authenticated-orcid":false,"given":"Melanie","family":"Brugger","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, School of Medicine and Health, Technical University of Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"issue":"11","key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/nrm4063","article-title":"Nonsense\u2010Mediated mRNA Decay: An Intricate Machinery That Shapes 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