{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T16:39:29Z","timestamp":1784219969338,"version":"3.55.0"},"reference-count":12,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T00:00:00Z","timestamp":1693872000000},"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":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Missense variants in the <jats:italic>RNF13<\/jats:italic> gene have been previously known to cause congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive through a gain\u2010of\u2010function disease mechanism. Here, we identify a nonsense variant, expected to result in protein truncation, in a similarly affected patient. We show that this nonsense variant, residing in the terminal exon, is likely to escape nonsense\u2010mediated decay while removing a critical region for protein function, thus resulting in a gain\u2010of\u2010function effect. We review the literature and disease databases and identify several other affected individuals with overlapping phenotypes carrying distinct truncating variants in the terminal exon upstream of the putative critical region. Furthermore, we analyze truncating variants from the general population, namely, the Genome Aggregation Database (gnomAD), and provide additional evidence supporting our hypothesis, and ruling out haploinsufficiency as an alternative disease mechanism. In summary, our case report, literature review, and analysis of disease and population databases strongly support the hypothesis that heterozygous gain\u2010of\u2010function variants in a critical region of <jats:italic>RNF13<\/jats:italic> cause congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive.<\/jats:p>","DOI":"10.1002\/ajmg.a.63390","type":"journal-article","created":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T12:17:00Z","timestamp":1693916220000},"page":"2723-2727","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Heterozygous gain of function variants in a critical region of <scp><i>RNF13<\/i><\/scp> cause congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive"],"prefix":"10.1002","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7679-3073","authenticated-orcid":false,"given":"Alan","family":"Taylor","sequence":"first","affiliation":[{"name":"Al Jalila Genomics Center of Excellence Al Jalila Children's Specialty Hospital  Dubai United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawan S.","family":"Kashyape","sequence":"additional","affiliation":[{"name":"Neurology Department Al Jalila Children's Specialty Hospital  Dubai United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchi","family":"Jain","sequence":"additional","affiliation":[{"name":"Al Jalila Genomics Center of Excellence Al Jalila Children's Specialty Hospital  Dubai United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha","family":"El Naofal","sequence":"additional","affiliation":[{"name":"Al Jalila Genomics Center of Excellence Al Jalila Children's Specialty Hospital  Dubai United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad Abou","family":"Tayoun","sequence":"additional","affiliation":[{"name":"Al Jalila Genomics Center of Excellence Al Jalila Children's Specialty Hospital  Dubai United Arab Emirates"},{"name":"Center for Genomic Discovery Mohammed Bin Rashid University of Medicine and Health Sciences  Dubai United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,5]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2009.06913.x"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2010.07924.x"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2021.11.020"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10113063"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-017-0486-3"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.11.018"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-023-01157-8"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg-2022-108645"},{"key":"e_1_2_8_10_1","doi-asserted-by":"crossref","unstructured":"Korff C. Ranza E. Blanc X. Santoni F. &Antonarakis S.(2022).Encephalopathy with epilepsy and movement disorder related to RNF13: Case Report. inAbstracts of the 48th Annual Meeting of the SENP (Soci\u00e9t\u00e9 Europ\u00e9enne De Neurologie P\u00e9diatrique).https:\/\/doi.org\/10.1055\/s-0042-1746215","DOI":"10.1055\/s-0042-1746215"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1127085"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3739"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2008.285"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.63390","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T06:11:34Z","timestamp":1697263894000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.63390"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,5]]},"references-count":12,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["10.1002\/ajmg.a.63390"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.63390","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,5]]},"assertion":[{"value":"2023-01-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}