{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:37:21Z","timestamp":1792805841632,"version":"4.5.0"},"reference-count":30,"publisher":"BMJ","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2013,4,18]]},"published-print":{"date-parts":[[2013,8]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Kaufman oculocerebrofacial syndrome (KOS) is a developmental disorder characterised by reduced growth, microcephaly, ocular anomalies (microcornea, strabismus, myopia, and pale optic disk), distinctive facial features (narrow palpebral fissures, telecanthus, sparse and laterally broad eyebrows, preauricular tags, and micrognathia), mental retardation, and generalised hypotonia. KOS is a rare, possibly underestimated condition, with fewer than 10 cases reported to date. Here we investigate the molecular cause underlying KOS.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>An exome sequencing approach was used on a single affected individual of an Italian consanguineous family coupled with mutation scanning using Sanger sequencing on a second unrelated subject with clinical features fitting the disorder.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Exome sequencing was able to identify homozygosity for a novel truncating mutation (c.556C&gt;T, p.Arg186stop) in UBE3B, which encodes a widely expressed HECT (homologous to the\u00a0E6-AP\u00a0carboxyl\u00a0terminus) domain E3 ubiquitin-protein ligase. Homozygosity for a different nonsense lesion affecting the gene (c.1166G&gt;A, p.Trp389stop) was documented in the second affected subject, supporting the recessive mode of inheritance of the disorder. Mutation scanning of the entire <jats:italic>UBE3B<\/jats:italic> coding sequence on a selected cohort of subjects with features overlapping, in part, those recurring in KOS did not reveal disease-causing mutations, suggesting phenotypic homogeneity of <jats:italic>UBE3B<\/jats:italic> lesions.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>Our data provide evidence that KOS is caused by UBE3B loss of function, and further demonstrate the impact of misregulation of protein ubiquitination on development and growth. The available clinical records, including those referring to four <jats:italic>UBE3B<\/jats:italic> mutation-positive subjects recently described as belonging to a previously unreported entity, which fits KOS, document the clinical homogeneity of this disorder.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmedgenet-2012-101405","type":"journal-article","created":{"date-parts":[[2013,5,18]],"date-time":"2013-05-18T00:24:38Z","timestamp":1368836678000},"page":"493-499","source":"Crossref","is-referenced-by-count":45,"title":["Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome"],"prefix":"10.1136","volume":"50","author":[{"given":"Elisabetta","family":"Flex","sequence":"first","affiliation":[{"name":"Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanit\u00e0, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ciolfi","sequence":"additional","affiliation":[{"name":"Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanit\u00e0, Rome, Italy"},{"name":"Dipartimento di Medicina Molecolare, Universit\u00e0 \u201cLa Sapienza\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Caputo","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale, Universit\u00e0 \u201cLa Sapienza\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Fodale","sequence":"additional","affiliation":[{"name":"Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanit\u00e0, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Leoni","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Pediatriche, Universit\u00e0 Cattolica del Sacro Cuore, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Melis","sequence":"additional","affiliation":[{"name":"Dipartimento di Pediatria, Facolt\u00e0 di Medicina e Chirurgia, Universit\u00e0 \u201cFederico II\u201d, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Francesca","family":"Bedeschi","sequence":"additional","affiliation":[{"name":"UOD Genetica Medica, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Mazzanti","sequence":"additional","affiliation":[{"name":"Dipartimento di Pediatria, Universit\u00e0 degli Studi di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Pizzuti","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale, Universit\u00e0 \u201cLa Sapienza\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanit\u00e0, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Zampino","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Pediatriche, Universit\u00e0 Cattolica del Sacro Cuore, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2013,5,17]]},"reference":[{"key":"2025101713455659000_50.8.493.1","first-page":"135","article-title":"An oculocerebrofacial syndrome","volume":"7","author":"Kaufman","year":"1971","journal-title":"Birth Defects Orig Art 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Branchial arch and oro-acral disorders. In: Gorlin RJ Hennekam RCM , eds. Syndromes of the head and neck. 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