POU3F3-related disorder: Defining the phenotype and expanding the molecular spectrum.

Autor: Rossi A; Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, member of the ERN-EpiCARE, Dianalund, Denmark.; Pediatric Clinic, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy., Blok LS; Human Genetics Department, Radboud University Medical Center, Nijmegen, the Netherlands., Neuser S; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Klöckner C; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Platzer K; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Faivre LO; Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Centre Hospitalier Universitaire Dijon, Dijon, France.; Genetics of Developmental Disorders Team, INSERM - Bourgogne Franche-Comté University, UMR 1231 GAD, Dijon, France., Weigand H; Department of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Dr. von Hauner's Children's Hospital, University of Munich, Munich, Germany., Dentici ML; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.; Medical Genetics Unit, Academic Department of Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Tartaglia M; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy., Niceta M; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy., Alfieri P; Child and Adolescent Neuropsychiatry Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Srivastava S; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA., Coulter D; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA., Smith L; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA., Vinorum K; Rikshospitalet, Oslo University Hospital, Oslo, Norway., Cappuccio G; Department of Translational Medicine, Federico II University, Naples, Italy.; Telethon Institute of Genetics and Medicine, Naples, Italy., Brunetti-Pierri N; Department of Translational Medicine, Federico II University, Naples, Italy.; Telethon Institute of Genetics and Medicine, Naples, Italy.; Scuola Superiore Meridionale, School for Advanced Studies, Naples, Italy., Torun D; Department of Medical Genetics, Gülhane Faculty of Medicine, University of Health Sciences, Ankara, Turkey., Arslan M; Department of Pediatric Neurology, Gülhane Faculty of Medicine, University of Health Sciences, Ankara, Turkey., Lauridsen MF; Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark., Murch O; All Wales Medical Genomics Service, University Hospital of Wales, Cardiff, UK., Irving R; All Wales Medical Genomics Service, University Hospital of Wales, Cardiff, UK., Lynch SA; Children's Health Ireland at Crumlin, Dublin 12, Ireland., Mehta SG; Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Carmichael J; Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Zonneveld-Huijssoon E; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., de Vries B; Human Genetics Department, Radboud University Medical Center, Nijmegen, the Netherlands., Kleefstra T; Human Genetics Department, Radboud University Medical Center, Nijmegen, the Netherlands., Johannesen KM; Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, member of the ERN-EpiCARE, Dianalund, Denmark.; Department of Genetics, University Hospital of Copenhagen, Copenhagen, Denmark., Westphall IT; Department of Paediatrics, Copenhagen University Hospital, Hvidovre, Denmark., Hughes SS; Division of Genetics, Children's Mercy Kansas City, Kansas City, Missouri, USA., Smithson S; Department of Clinical Genetics, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK., Evans J; Bristol Genetics Laboratory, North Bristol NHS Trust, Pathology Sciences Building, Southmead Hospital, Bristol, UK., Dudding-Byth T; NSW Genetics of Learning Disability (GOLD) Service, University of Newcastle, New South Wales, Australia., Simon M; Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands., van Binsbergen E; Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands., Herkert JC; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Beunders G; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Oppermann H; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Bakal M; Clinic of Radiology, University of Health Sciences Turkey, Haseki Training and Research Hospital, Istanbul, Turkey., Møller RS; Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, member of the ERN-EpiCARE, Dianalund, Denmark.; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark., Rubboli G; Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, member of the ERN-EpiCARE, Dianalund, Denmark.; Institute of Clinical Medicine, Copenhagen University, Copenhagen, Denmark., Bayat A; Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, member of the ERN-EpiCARE, Dianalund, Denmark.; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: Clinical genetics [Clin Genet] 2023 Aug; Vol. 104 (2), pp. 186-197. Date of Electronic Publication: 2023 May 10.
DOI: 10.1111/cge.14353
Abstrakt: POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.
(© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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