{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T02:45:01Z","timestamp":1789785901715,"version":"4.0.1"},"reference-count":32,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,3,25]],"date-time":"2020-03-25T00:00:00Z","timestamp":1585094400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["91217045"],"award-info":[{"award-number":["91217045"]}],"id":[{"id":"10.13039\/501100001826","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":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>DNA double\u2010strand breaks (DSBs) are highly toxic DNA lesions that can lead to chromosomal instability, loss of genes and cancer. The MRE11\/RAD50\/NBN (MRN) complex is keystone involved in signaling processes inducing the repair of DSB by, for example, in activating pathways leading to homologous recombination repair and nonhomologous end joining. Additionally, the MRN complex also plays an important role in the maintenance of telomeres and can act as a stabilizer at replication forks. Mutations in <jats:italic>NBN<\/jats:italic> and <jats:italic>MRE11<\/jats:italic> are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)\u2010like disorder, respectively. So far, only one single patient with biallelic loss of function variants in <jats:italic>RAD50<\/jats:italic> has been reported presenting with features classified as NBS\u2010like disorder. Here, we report a long\u2010term follow\u2010up of an unrelated patient with facial dysmorphisms, microcephaly, skeletal features, and short stature who is homozygous for a novel variant in <jats:italic>RAD50<\/jats:italic>. We could show that this variant, c.2524G\u2009&gt;\u2009A in exon 15 of the <jats:italic>RAD50<\/jats:italic> gene, induces aberrant splicing of <jats:italic>RAD50<\/jats:italic> mRNA mainly leading to premature protein truncation and thereby, most likely, to loss of RAD50 function. Using patient\u2010derived primary fibroblasts, we could show abnormal radioresistant DNA synthesis confirming pathogenicity of the identified variant. Immunoblotting experiments showed strongly reduced protein levels of RAD50 in the patient\u2010derived fibroblasts and provided evidence for a markedly reduced radiation\u2010induced AT\u2010mutated signaling. Comparison with the previously reported case and with patients presenting with NBS confirms that <jats:italic>RAD50<\/jats:italic> mutations lead to a similar, but distinctive phenotype.<\/jats:p>","DOI":"10.1002\/ajmg.a.61570","type":"journal-article","created":{"date-parts":[[2020,3,25]],"date-time":"2020-03-25T13:25:38Z","timestamp":1585142738000},"page":"1378-1386","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Human <scp><i>RAD50<\/i><\/scp> deficiency: Confirmation of a distinctive phenotype"],"prefix":"10.1002","volume":"182","author":[{"given":"Avi\u00ebl","family":"Ragamin","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics Erasmus MC University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6khan","family":"Yigit","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine","family":"Bousset","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Beleggia","sequence":"additional","affiliation":[{"name":"Clinic I of Internal Medicine University Hospital Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frans W.","family":"Verheijen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Erasmus MC University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Claire Y.","family":"de Wit","sequence":"additional","affiliation":[{"name":"Department of Child Neurology Sophia Children's Hospital, Erasmus MC University Medical Center  Rotterdam Netherlands"},{"name":"ENCORE Expertise Center for Neurodevelopmental Disorders  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim M.","family":"Strom","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Helmholtz Zentrum M\u00fcnchen  Neuherberg Germany"},{"name":"Institute of Human Genetics Technische Universit\u00e4t M\u00fcnchen  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thilo","family":"D\u00f6rk","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Wollnik","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"},{"name":"Cluster of Excellence \"Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells\" (MBExC) University of G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1211-9979","authenticated-orcid":false,"given":"Grazia M. 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