Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt.

Autor:	Shepherdson JL; Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, USA., Hutchison K; Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Don DW; Department of Biology, Chungnam National University, Daejeon 34134, Korea., McGillivray G; Victorian Clinical Genetics Services, Parkville, VIC 3052, Australia; Murdoch Children's Research Institute, Parkville, VIC 3052, Australia., Choi TI; Department of Biology, Chungnam National University, Daejeon 34134, Korea., Allan CA; Hudson Institute of Medical Research, Monash University, and Department of Endocrinology, Monash Health, Melbourne, Australia., Amor DJ; Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Parkville 3052, VIC, Australia., Banka S; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK., Basel DG; Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA., Buch LD; Greenwood Genetic Center, Greenwood, SC, USA., Carere DA; GeneDx, Gaithersburg, MD 20877, USA., Carroll R; Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia., Clayton-Smith J; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK., Crawford A; Medical Genomics Research, Illumina Inc, San Diego, CA, USA., Dunø M; Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark., Faivre L; Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, Dijon, France; INSERM UMR1231, Equipe GAD, Université de Bourgogne-Franche Comté, 21000 Dijon, France., Gilfillan CP; Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia; Department of Endocrinology, Eastern Health, Box Hill Hospital, Melbourne, VIC, Australia., Gold NB; Harvard Medical School, Boston, MA, USA; Division of Medical Genetics and Metabolism, Massachusetts General Hospital, Boston, MA, USA., Gripp KW; Division of Medical Genetics, Nemours Children's Hospital, Wilmington, DE, USA., Hobson E; Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK., Holtz AM; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA., Innes AM; Departments of Medical Genetics and Pediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada., Isidor B; Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France; Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, 44000 Nantes, France., Jackson A; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK., Katsonis P; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Amel Riazat Kesh L; Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK., Küry S; Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000 Nantes, France; Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, 44000 Nantes, France., Lecoquierre F; Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, 76000 Rouen, France., Lockhart P; Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Parkville 3052, VIC, Australia., Maraval J; Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, Dijon, France; INSERM UMR1231, Equipe GAD, Université de Bourgogne-Franche Comté, 21000 Dijon, France., Matsumoto N; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan., McCarrier J; Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA., McCarthy J; Department of Endocrinology, Eastern Health, Box Hill Hospital, Melbourne, VIC, Australia., Miyake N; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan., Moey LH; Department of Genetics, Penang General Hospital, George Town, Penang, Malaysia., Németh AH; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Østergaard E; Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., Patel R; Medical Genetics, Kaiser Permanente Oakland Medical Center, Oakland, CA, USA., Pope K; Murdoch Children's Research Institute, Parkville, VIC 3052, Australia., Posey JE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Schnur RE; GeneDx, Gaithersburg, MD 20877, USA., Shaw M; Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia., Stolerman E; Greenwood Genetic Center, Greenwood, SC, USA., Taylor JP; Medical Genomics Research, Illumina Inc, San Diego, CA, USA., Wadman E; Division of Medical Genetics, Nemours Children's Hospital, Wilmington, DE, USA., Wakeling E; North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK., White SM; Victorian Clinical Genetics Services, Parkville, VIC 3052, Australia; Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Parkville 3052, VIC, Australia., Wong LC; Medical Genetics, Kaiser Permanente Downey Medical Center, Downey, CA, USA., Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA., Lichtarge O; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Corbett MA; Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia., Gecz J; Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia., Nicolet CM; Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Farnham PJ; Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Kim CH; Department of Biology, Chungnam National University, Daejeon 34134, Korea. Electronic address: zebrakim@cnu.ac.kr., Shinawi M; Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: mshinawi@wustl.edu.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2024 Mar 07; Vol. 111 (3), pp. 487-508. Date of Electronic Publication: 2024 Feb 06.
DOI:	10.1016/j.ajhg.2024.01.007
Abstrakt:	Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum, and ear abnormalities. Hyperparathyroidism was found in four families with missense variants, and enrichment of different tumor types was observed. In molecular studies, DNA-binding domain variants elicited differential expression of a small set of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, providing additional evidence for the functional significance of ZFX. Our clinical and experimental data support that variants in ZFX are associated with an X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism. Competing Interests: Declaration of interests D.A.C. and R.E.S. are employees of GeneDx, LLC. A.C. and J.P.T. are employees and shareholders of Illumina, Inc. L.D.B. performs advisory board, consulting, and speaking arrangement work unrelated to the present study for Sanofi S.A., Horizon Therapeutics, Amicus Therapeutics, and Chiesi Farmaceutici S.p.A. N.B.G. has received personal fees from Pfizer Inc. and RCG Consulting for work unrelated to the present study. J.R.L. has stock ownership in 23andMe and is a paid consultant to Genome International. (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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