{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:30Z","timestamp":1792787310192,"version":"4.5.0"},"reference-count":50,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Eva Luise and Horst K\u00f6hler foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["Recon4IMD -GAP-101080997"],"award-info":[{"award-number":["Recon4IMD -GAP-101080997"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"name":"German Research Foundation","award":["DFG \/ EJP-RD Artemis: 542553983"],"award-info":[{"award-number":["DFG \/ EJP-RD Artemis: 542553983"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2026,5,28]]},"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Neurodevelopmental disorders are one of the most prevalent reasons for genetic testing in childhood. Despite the identification of over 1950 associated genes, many proposed candidate genes lack convincing gene-disease validity. The gene\n                      <jats:italic>PREP<\/jats:italic>\n                      encodes the broadly expressed prolyl endopeptidase whose exact function remains largely unknown. A homozygous\n                      <jats:italic>PREP<\/jats:italic>\n                      variant has been reported once as a candidate gene in two siblings with intellectual disability but no functional studies were conducted.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Exome and trio genome sequencing were performed in two unrelated families as part of larger cohorts. Segregation analysis, RNA sequencing and immunoblots were performed to further examine the pathogenicity of detected\n                      <jats:italic>PREP<\/jats:italic>\n                      variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We report three individuals from two unrelated families who presented with intellectual disability, behavioural abnormalities, strabismus, generalised muscular hypotonia, dysmorphic facial features and epilepsy. Exome and genome sequencing identified two different homozygous rare\n                      <jats:italic>PREP<\/jats:italic>\n                      variants: c.1570_1573dup, p.(Asn525Thrfs*5) and c.1839-2A&gt;G, p.?. RNA sequencing confirmed the detected intronic variant to result in two aberrant mRNA isoforms. In patient-derived cells immunoblots showed absence of PREP protein.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our data suggest PREP deficiency as the underlying cause of a syndromic neurodevelopmental disorder.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2026-111501","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T17:20:44Z","timestamp":1782494444000},"page":"605-612","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of biallelic loss-of-function\n                    <i>PREP<\/i>\n                    variants in three individuals with syndromic intellectual disability"],"prefix":"10.1136","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3728-552X","authenticated-orcid":false,"given":"Erik","family":"Hertstein","sequence":"first","affiliation":[{"name":"Institute of Medical Genetics and Human Genetics, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6960-8837","authenticated-orcid":false,"given":"Miriam","family":"Bertrand","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0391-1497","authenticated-orcid":false,"given":"Johannes","family":"Kopp","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2628-2890","authenticated-orcid":false,"given":"Oliver","family":"K\u00fcchler","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Human Genetics, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany"},{"name":"Exploratory Diagnostic Sciences (EDS), Berlin Institute of Health at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8116-9032","authenticated-orcid":false,"given":"Nicolai","family":"von K\u00fcgelgen","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Human Genetics, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and 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