{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:54:39Z","timestamp":1790391279475,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T00:00:00Z","timestamp":1639699200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Variants in transcription factor <jats:italic>GLI2<\/jats:italic> have been associated with hypopituitarism and structural brain abnormalities, occasionally including holoprosencephaly (HPE). Substantial phenotypic variability and nonpenetrance have been described, posing difficulties in the counseling of affected families. We present three individuals with novel likely pathogenic <jats:italic>GLI2<\/jats:italic> variants, two with truncating and one with a de novo missense variant p.(Ser548Leu), and review the literature for comprehensive phenotypic descriptions of individuals with confirmed pathogenic (a) intragenic <jats:italic>GLI2<\/jats:italic> variants and (b) chromosome 2q14.2 deletions encompassing only <jats:italic>GLI2<\/jats:italic>. We show that most of the 31 missense variants previously reported as pathogenic are likely benign or, at most, low\u2010risk variants. Four Zn\u2010finger variants: p.(Arg479Gly), p.(Arg516Pro), p.(Gly518Lys), and p.(Tyr575His) were classified as likely pathogenic, and three other variants as possibly pathogenic: p.(Pro253Ser), p.(Ala593Val), and p.(Pro1243Leu). We analyze the phenotypic descriptions of 60 individuals with pathogenic <jats:italic>GLI2<\/jats:italic> variants and evidence a morbidity spectrum that includes hypopituitarism (58%), HPE (6%) or other brain structure abnormalities (15%), orofacial clefting (17%) and dysmorphic facial features (35%). We establish that truncating and Zn\u2010finger variants in <jats:italic>GLI2<\/jats:italic> are associated with a high risk of hypopituitarism, and that a solitary median maxillary central incisor is part of the <jats:italic>GLI2<\/jats:italic>\u2010related phenotypic variability. The most prevalent phenotypic feature is post\u2010axial polydactyly (65%) which is also the mildest phenotypic expression of the condition, reported in many parents of individuals with systemic findings. Our approach clarifies clinical risks and the important messages to discuss in counseling for a pathogenic <jats:italic>GLI2<\/jats:italic> variant.<\/jats:p>","DOI":"10.1002\/ajmg.a.62611","type":"journal-article","created":{"date-parts":[[2021,12,18]],"date-time":"2021-12-18T07:54:12Z","timestamp":1639814052000},"page":"1065-1074","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Truncating and zinc\u2010finger variants in <scp><i>GLI2<\/i><\/scp> are associated with hypopituitarism"],"prefix":"10.1002","volume":"188","author":[{"given":"Megan L.","family":"Corder","sequence":"first","affiliation":[{"name":"Faculty of Health and Medicine, Lancaster University  Lancaster UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siren","family":"Berland","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Haukeland University Hospital  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jostein A.","family":"F\u00f8rsvoll","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Stavanger University Hospital  Stavanger Norway"},{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indraneel","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Medicine and Health, Division of Developmental Biology and Medicine University of Manchester and Manchester Academic Health Science Centre, Royal Manchester Children's Hospital, Manchester University Hospitals NHS Foundation Trust  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phil","family":"Murray","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Medicine and Health, Division of Developmental Biology and Medicine University of Manchester and Manchester Academic Health Science Centre, Royal Manchester Children's Hospital, Manchester University Hospitals NHS Foundation Trust  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirik","family":"Bratland","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Gokhale","sequence":"additional","affiliation":[{"name":"North West Genomic Laboratory Hub Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Houge","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Haukeland University Hospital  Bergen Norway"},{"name":"Division of Evolution, Infection and Genomics, School of Biological Sciences University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8890-7544","authenticated-orcid":false,"given":"Sofia","family":"Douzgou","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Haukeland University Hospital  Bergen Norway"},{"name":"Division of Evolution, Infection and Genomics, School of Biological Sciences University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,12,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1530\/JME-15-0009"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.13914"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2013-102249"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2010.01606.x"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0242358"},{"issue":"4","key":"e_1_2_10_7_1","first-page":"706","article-title":"GLI2 mutations as a cause of hypopituitarism","volume":"9","author":"Cohen L. 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