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At birth, they both presented with bilateral cryptorchidism and malformations. Since early adulthood, they developed a slowly progressive neurological syndrome, with cerebellar and pyramidal signs, cognitive impairment, and depression. Dilating cardiomyopathy is also present in both. By whole\u2010exome sequencing, we found a homozygous nucleotide change in\n                    <jats:italic>XRCC4<\/jats:italic>\n                    (c.673C&gt;T), predicted to introduce a premature stop codon (p.R225*).\n                    <jats:italic>XRCC4<\/jats:italic>\n                    transcript levels were profoundly reduced, and the protein was undetectable in patients' skin fibroblasts. XRCC4 plays an important role in non\u2010homologous end joining of DNA double\u2010strand breaks (DSB), a system that is involved in repairing DNA damage from, for example, ionizing radiations. Gamma\u2010irradiated mutant cells demonstrated reduction, but not abolition, of DSB repair. In contrast with embryonic lethality of the\n                    <jats:italic>Xrcc4<\/jats:italic>\n                    KO mouse, nonsense mutations in human XRCC4 have recently been associated with primordial dwarfism and, in our cases, with adult\u2010onset neurological impairment, suggesting an important role for DNA repair in the brain. Surprisingly, neither immunodeficiency nor predisposition to malignancy was reported in these patients.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201404803","type":"journal-article","created":{"date-parts":[[2015,4,14]],"date-time":"2015-04-14T20:51:14Z","timestamp":1429044674000},"page":"918-929","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["A nonsense mutation of human XRCC4 is associated with adult\u2010onset progressive encephalocardiomyopathy"],"prefix":"10.1038","volume":"7","author":[{"given":"Leonardo","family":"Bee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Nasca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Zanolini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Cendron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pio","family":"d'Adamo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolfo","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costanza","family":"Lamperti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Celotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Ghezzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Zeviani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,4,14]]},"reference":[{"key":"BFEMMM201404803_CR1","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/nature05164","volume":"443","author":"I Ahel","year":"2006","unstructured":"Ahel I, Rass U, El\u2010Khamisy SF, Katyal S, Clements PM, McKinnon PJ, Caldecott KW, West SC (2006) The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates. 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