{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T21:24:54Z","timestamp":1783632294807,"version":"3.55.0"},"reference-count":15,"publisher":"Wiley","issue":"5-6","license":[{"start":{"date-parts":[[2022,3,13]],"date-time":"2022-03-13T00:00:00Z","timestamp":1647129600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    We report four children from three related families who presented with a similar phenotype characterized by developmental delay, hypotonia, seizures, failure\u2010to\u2010thrive, strabismus, drooling, recurrent otitis media, hearing impairment, and genitourinary malformations. They also shared common facial features including arched eyebrows, prominent eyes, broad nasal bridge, low\u2010hanging columella, open mouth, thick lower lip, protruding tongue, large low\u2010set ears, and parietal bossing. Exome sequencing for affected individuals revealed a homozygous frame\u2010shift variant, c.1833del; p.(Thr612Glnfs*22), in\n                    <jats:italic>PROSER1<\/jats:italic>\n                    which encodes the proline and serine rich protein 1 (PROSER1). PROSER1 has recently been found to be part of the histone methyltransferases KMT2C\/KMT2D complexes. PROSER1 stabilizes TET2, a member of the TET family of DNA demethylases which is involved in recruiting the enhancer\u2010associated KMT2C\/KMT2D complexes and mediating DNA demethylation, activating gene expression. Therefore, PROSER1 may play vital and potentially general roles in gene regulation, consistent with the wide phenotypic spectrum observed in the individuals presented here. The consistent phenotype, the loss\u2010of\u2010function predicted from the frame\u2010shift, the co\u2010segregation of the phenotype in our large pedigree, the vital role of\n                    <jats:italic>PROSER1<\/jats:italic>\n                    in gene regulation, and the association of related genes with neurodevelopmental disorders argue for the loss of PROSER1 to be the cause for a novel recognizable syndrome.\n                  <\/jats:p>","DOI":"10.1111\/cge.14126","type":"journal-article","created":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T03:20:20Z","timestamp":1646104820000},"page":"565-570","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A homozygous frame\u2010shift variant in\n                    <scp>\n                      <i>PROSER1<\/i>\n                    <\/scp>\n                    is associated with developmental delay, hypotonia, genitourinary malformations, and distinctive facial features"],"prefix":"10.1111","volume":"101","author":[{"given":"Azza","family":"Salah","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University Hospital Sharjah  Sharjah United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Almannai","sequence":"additional","affiliation":[{"name":"Department of Genetics and Precision Medicine King Abdullah Specialized Children's Hospital  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mode","family":"Al Ojaimi","sequence":"additional","affiliation":[{"name":"College of Medicine University of Sharjah  Sharjah United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy","family":"Radefeldt","sequence":"additional","affiliation":[{"name":"Centogene GmbH  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishtha","family":"Gulati","sequence":"additional","affiliation":[{"name":"Centogene GmbH  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Centogene GmbH  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salem","family":"Alawbathani","sequence":"additional","affiliation":[{"name":"Centogene GmbH  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruslan","family":"Al\u2010Ali","sequence":"additional","affiliation":[{"name":"Centogene GmbH  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7061-2895","authenticated-orcid":false,"given":"Christian","family":"Beetz","sequence":"additional","affiliation":[{"name":"Centogene GmbH  Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5737-5271","authenticated-orcid":false,"given":"Ayman W.","family":"El\u2010Hattab","sequence":"additional","affiliation":[{"name":"College of Medicine University of Sharjah  Sharjah United Arab Emirates"},{"name":"Department of Clinical Genetics, University Hospital Sharjah  Sharjah United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,13]]},"reference":[{"issue":"11","key":"e_1_2_9_2_1","first-page":"2413","article-title":"Meta\u2010analysis and multidisciplinary consensus statement: exome sequencing is a first\u2010tier clinical diagnostic test for individuals with neurodevelopmental disorders","volume":"21","author":"Srivastava S","year":"2019","journal-title":"Genet Med Off J Am Coll Med Genet."},{"issue":"11","key":"e_1_2_9_3_1","first-page":"2029","article-title":"Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence\u2010based clinical guideline of the American College of Medical Genetics and Genomics (ACMG)","volume":"23","author":"Manickam K","year":"2021","journal-title":"Genet Med Off J Am Coll Med Genet"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2017.116"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-017-1821-8"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13690"},{"issue":"1","key":"e_1_2_9_7_1","first-page":"53","article-title":"Development of an evidence\u2010based algorithm that optimizes sensitivity and specificity in ES\u2010based diagnostics of a clinically heterogeneous patient population","volume":"21","author":"Bauer P","year":"2019","journal-title":"Genet Med Off J Am Coll Med Genet."},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202101228"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.190629.115"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1606857113"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.06.008"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.10.010"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.05.003"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.646"},{"issue":"7","key":"e_1_2_9_15_1","first-page":"1202","article-title":"Clinical delineation, sex differences, and genotype\u2010phenotype correlation in pathogenic KDM6A variants causing X\u2010linked Kabuki syndrome type 2","volume":"23","author":"Faundes V","year":"2021","journal-title":"Genet Med Off J Am Coll Med Genet."},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.12.007"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.14126","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.14126","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.14126","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T13:49:44Z","timestamp":1692971384000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.14126"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,13]]},"references-count":15,"journal-issue":{"issue":"5-6","published-print":{"date-parts":[[2022,5]]}},"alternative-id":["10.1111\/cge.14126"],"URL":"https:\/\/doi.org\/10.1111\/cge.14126","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/CGE.14126\/v1\/review3","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.14126\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.14126\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.14126\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.14126\/v2\/decision1","asserted-by":"object"}]},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,13]]},"assertion":[{"value":"2022-01-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}