{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T14:09:46Z","timestamp":1781100586722,"version":"3.54.1"},"reference-count":9,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T00:00:00Z","timestamp":1729123200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T00:00:00Z","timestamp":1729123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100007787","name":"National Research Centre","doi-asserted-by":"publisher","award":["13060144"],"award-info":[{"award-number":["13060144"]}],"id":[{"id":"10.13039\/100007787","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007787","name":"National Research Centre","doi-asserted-by":"publisher","award":["13060144"],"award-info":[{"award-number":["13060144"]}],"id":[{"id":"10.13039\/100007787","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007787","name":"National Research Centre","doi-asserted-by":"publisher","award":["13060144"],"award-info":[{"award-number":["13060144"]}],"id":[{"id":"10.13039\/100007787","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Hum Genet"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Biallelic loss of function variants in <jats:italic>ESAM<\/jats:italic> (endothelial cell adhesion molecule) have recently been reported in 14 individuals (9 families) presenting with prenatal intracranial hemorrhage. Here, we describe four patients from two unrelated families in whom three of them presented with variable onset encephalopathy and seizures while one only displayed profound delay without seizures. Brain MRI showed variable onset intracranial hemorrhage that evolved to hydrocephalus in 3 patients, whereas hemosiderin deposits, white matter volume loss, and porencephalic cysts were noted in one patient. Unlike the majority of described cases, the youngest brother of the first family did not show microcephaly and failure to thrive. Exome sequencing identified two novel homozygous <jats:italic>ESAM<\/jats:italic> variants. A splice variant (c.731-2A&gt;G) was identified in one family which was confirmed by investigating the patient\u2019s mRNA to result in exon skipping and early protein truncation. In addition, a missense variant (c.561G&gt;C; p.Trp187Cys) was identified in the other family, which is the first disease causing missense variant to be described in patients with <jats:italic>ESAM<\/jats:italic> deficient phenotype. In addition, a maternally inherited pathogenic <jats:italic>MC4R<\/jats:italic> variant (c.811T&gt;C; p.Cys271\u2009Arg) was also identified in the youngest brother of the first family. Variants in the <jats:italic>MC4R<\/jats:italic> gene are associated with a non-syndromic form of obesity that could explain the unusual macrocephaly and obesity. Our work establishes <jats:italic>ESAM<\/jats:italic> as a tight junction gene that can present with variable neuroradiological and clinical phenotypes when mutated. Moreover, it refines the phenotype of this ultrarare syndrome and extends the number and type of variants described to date.<\/jats:p>","DOI":"10.1038\/s10038-024-01297-8","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T03:49:19Z","timestamp":1729136959000},"page":"67-74","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Novel homozygous ESAM variants in two families with perinatal strokes showing variable neuroradiologic and clinical findings"],"prefix":"10.1038","volume":"70","author":[{"given":"Ghada M. H.","family":"Abdel-Salam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa","family":"Esmail","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina","family":"Nagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherif F.","family":"Abdel-Ghafar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed S.","family":"Abdel-Hamid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,17]]},"reference":[{"key":"1297_CR1","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1016\/j.ajhg.2010.10.026","volume":"87","author":"GH Mochida","year":"2010","unstructured":"Mochida GH, Ganesh VS, Felie JM, Gleason D, Hill RS, Clapham KR, et al. A homozygous mutation in the tight-junction protein JAM3 causes hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Am J Hum Genet. 2010;87:882\u20139. https:\/\/doi.org\/10.1016\/j.ajhg.2010.10.026","journal-title":"Am J Hum Genet"},{"key":"1297_CR2","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1016\/j.ajhg.2023.03.005","volume":"110","author":"M Lecca","year":"2023","unstructured":"Lecca M, Pehlivan D, Su\u00f1er DH, Weiss K, Coste T, Zweier M, et al. Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage. Am J Hum Genet. 2023;110:681\u201390.","journal-title":"Am J Hum Genet"},{"key":"1297_CR3","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/jhg.2017.4","volume":"62","author":"MS Abdel-Hamid","year":"2017","unstructured":"Abdel-Hamid MS, Abdel-Salam GMH, Issa MY, Emam BA, Zaki MS. Band-like calcification with simplified gyration and polymicrogyria: report of 10 new families and identification of five novel OCLN mutations. J Hum Genet. 2017;62:553\u20139. https:\/\/doi.org\/10.1038\/jhg.2017.4","journal-title":"J Hum Genet."},{"key":"1297_CR4","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1016\/j.ajhg.2020.02.007","volume":"106","author":"LV Schottlaender","year":"2020","unstructured":"Schottlaender LV, Abeti R, Jaunmuktane Z, Macmillan C, Chelban V, O\u2019Callaghan B, et al. Biallelic JAM2 variants lead to early-onset recessive primary familial brain calcification. Am J Hum Genet. 2020;106:412\u201321. https:\/\/doi.org\/10.1016\/j.ajhg.2020.02.007","journal-title":"Am J Hum Genet."},{"key":"1297_CR5","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s00439-023-02621-6","volume":"143","author":"MJ Alshammari","year":"2024","unstructured":"Alshammari MJ, Shamseldin HE, Essbaiheen F, Eltahir SH, Alruwaili AR, Abdulwahab F, et al. Genomic analysis of presumed perinatal stroke in Saudi Arabia reveals a strong monogenic contribution. Hum Genet. 2024;143:59\u201369. https:\/\/doi.org\/10.1007\/s00439-023-02621-6","journal-title":"Hum Genet"},{"key":"1297_CR6","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1056\/NEJMoa022050","volume":"348","author":"IS Farooqi","year":"2003","unstructured":"Farooqi IS, Keogh JM, Yeo GSH, Lank EJ, Cheetham T, O\u2019Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N. Engl J Med. 2003;348:1085\u201395.","journal-title":"N. Engl J Med"},{"key":"1297_CR7","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1002\/humu.22263","volume":"34","author":"NA Akawi","year":"2013","unstructured":"Akawi NA, Canpolat FE, White SM, Quilis-Esquerra J, Morales Sanchez M, Gamundi MJ, et al. Delineation of the clinical, molecular and cellular aspects of novel JAM3 mutations underlying the autosomal recessive hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Hum Mutat. 2013;34:498\u2013505. https:\/\/doi.org\/10.1002\/humu.22263","journal-title":"Hum Mutat"},{"key":"1297_CR8","doi-asserted-by":"publisher","first-page":"3129","DOI":"10.1002\/ajmg.a.62389","volume":"185A","author":"S Walker","year":"2021","unstructured":"Walker S, Lamoureux S, Khan T, Joynt ACM, Bradley M, Branson HM, et al. Genome sequencing for detection of pathogenic deep intronic variation: A clinical case report illustrating opportunities and challenges. Am J Med Genet Part A. 2021;185A:3129\u201335. https:\/\/doi.org\/10.1002\/ajmg.a.62389","journal-title":"Am J Med Genet Part A"},{"key":"1297_CR9","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-018-0654-1","volume":"19","author":"M Drabkin","year":"2018","unstructured":"Drabkin M, Birk OS, Birk R. Heterozygous versus homozygous phenotype caused by the same MC4R mutation: novel mutation affecting a large consanguineous kindred. 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