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Truncating and zinc-finger variants in GLI2 are associated with hypopituitarism.
Corder, Megan L; Berland, Siren; Førsvoll, Jostein A; Banerjee, Indraneel; Murray, Phil; Bratland, Eirik; Gokhale, David; Houge, Gunnar; Douzgou, Sofia.
Afiliação
  • Corder ML; Faculty of Health and Medicine, Lancaster University, Lancaster, UK.
  • Berland S; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
  • Førsvoll JA; Department of Pediatrics, Stavanger University Hospital, Stavanger, Norway.
  • Banerjee I; Department of Clinical Science, University of Bergen, Bergen, Norway.
  • Murray P; 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.
  • Bratland E; 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.
  • Gokhale D; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
  • Houge G; Department of Clinical Science, University of Bergen, Bergen, Norway.
  • Douzgou S; North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.
Am J Med Genet A ; 188(4): 1065-1074, 2022 04.
Article em En | MEDLINE | ID: mdl-34921505
ABSTRACT
Variants in transcription factor GLI2 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 GLI2 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 GLI2 variants and (b) chromosome 2q14.2 deletions encompassing only GLI2. We show that most of the 31 missense variants previously reported as pathogenic are likely benign or, at most, low-risk variants. Four Zn-finger 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 GLI2 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-finger variants in GLI2 are associated with a high risk of hypopituitarism, and that a solitary median maxillary central incisor is part of the GLI2-related phenotypic variability. The most prevalent phenotypic feature is post-axial 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 GLI2 variant.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Holoprosencefalia / Hipopituitarismo Tipo de estudo: Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Holoprosencefalia / Hipopituitarismo Tipo de estudo: Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article