{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T16:04:59Z","timestamp":1749830699688,"version":"3.37.3"},"reference-count":37,"publisher":"Cold Spring Harbor Laboratory","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cold Spring Harb Mol Case Stud"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:p>The ETS2 repressor factor (ERF) is a transcription factor in the RAS-MEK-ERK signal transduction cascade that regulates cell proliferation and differentiation, and pathogenic sequence variants in the <jats:italic>ERF<\/jats:italic> gene cause variable craniosynostosis inherited in an autosomal dominant pattern. The reported <jats:italic>ERF<\/jats:italic> variants are largely loss-of-function, implying haploinsufficiency as a primary disease mechanism; however, <jats:italic>ERF<\/jats:italic> gene deletions have not been reported previously. Here we describe three probands with macrocephaly, craniofacial dysmorphology, and global developmental delay. Clinical genetic testing for fragile X and other relevant sequencing panels were negative; however, chromosomal microarray identified heterozygous deletions (63.7\u2013583.2 kb) on Chromosome 19q13.2 in each proband that together included five genes associated with Mendelian diseases (<jats:italic>ATP1A3<\/jats:italic>, <jats:italic>ERF<\/jats:italic>, <jats:italic>CIC<\/jats:italic>, <jats:italic>MEGF8<\/jats:italic>, and <jats:italic>LIPE<\/jats:italic>). Parental testing indicated that the aberrations were apparently de novo in two of the probands and were inherited in the one proband with the smallest deletion. Deletion of <jats:italic>ERF<\/jats:italic> is consistent with the reported loss-of-function <jats:italic>ERF<\/jats:italic> variants, prompting clinical copy-number-variant classifications of likely pathogenic. Moreover, the recent characterization of heterozygous loss-of-function <jats:italic>CIC<\/jats:italic> sequence variants as a cause of intellectual disability and neurodevelopmental disorders inherited in an autosomal dominant pattern is also consistent with the developmental delays and intellectual disabilities identified among the two probands with <jats:italic>CIC<\/jats:italic> deletions. Taken together, this case series adds to the previously reported patients with <jats:italic>ERF<\/jats:italic> and\/or <jats:italic>CIC<\/jats:italic> sequence variants and supports haploinsufficiency of both genes as a mechanism for a variable syndromic cranial phenotype with developmental delays and intellectual disability inherited in an autosomal dominant pattern.<\/jats:p>","DOI":"10.1101\/mcs.a005991","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T21:20:26Z","timestamp":1623446426000},"page":"a005991","source":"Crossref","is-referenced-by-count":4,"title":["Deletion of <i>ERF<\/i> and <i>CIC<\/i> causes abnormal skull morphology and global developmental delay"],"prefix":"10.1101","volume":"7","author":[{"given":"Ram","family":"Singh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana S.A.","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cathryn","family":"Poulton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tina Duelund","family":"Hjortsh\u00f8j","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moe","family":"Akahira-Azuma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geetu","family":"Mendiratta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wahab A.","family":"Khan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitar N.","family":"Azmanov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen J.","family":"Woodward","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Kirchhoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisong","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Edelmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gareth","family":"Baynam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5720-1864","authenticated-orcid":false,"given":"Stuart A.","family":"Scott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8983-5466","authenticated-orcid":false,"given":"Ethylin Wang","family":"Jabs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"246","published-online":{"date-parts":[[2021,6,11]]},"reference":[{"key":"2021112406091254000_7.3.a005991.1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36274"},{"key":"2021112406091254000_7.3.a005991.2","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2016-104143"},{"key":"2021112406091254000_7.3.a005991.3","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23855"},{"key":"2021112406091254000_7.3.a005991.4","unstructured":"Brashear A , Sweadner KJ , Cook JF , Swoboda KJ , Ozelius L . 1993. 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