Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein
Authors
Elke de Boer, Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
Charlotte W. Ockeloen, Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands. Electronic address: Charlotte.Ockeloen@radboudumc.nl.
Rosalie A. Kampen, Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
Juliet E. Hampstead, Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.
Alexander J. Dingemans, Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
Dmitrijs Rots, Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
Lukas Lütje, Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
Tazeen Ashraf, Department of Clinical Genetics, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom; Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
Rachel Baker, Advocate Aurora HealthFollow
Mouna Barat-Houari, Genetic Laboratory of Rare and Autoinflammatory Diseases, Department of Medical Genetics, Rare Diseases and Personalized Medicine, Centre Hospitalier Universitaire de Montpellier, Montpellier, France.
Brad Angle, Advocate Aurora HealthFollow
Nicolas Chatron, Service de Génétique, Hospices Civils de Lyon, Bron, France; Institut NeuroMyoGene, CNRS UMR5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France.
Anne-Sophie Denommé-Pichon, Génétique des Anomalies du Développement, Université de Bourgogne Franche-Comté, UMR1231-Inserm, Dijon, France; Laboratoire de Génétique Chromosomique et Moléculaire, UF6254 Innovation en Diagnostic Génomique des Maladies Rares, Centre Hospitalier Universitaire de Dijon, Dijon, France.
Orrin Devinsky, Department of Neurology, NYU Grossman School of Medicine, NYU Langone Health, New York, NY.
Christèle Dubourg, Service de Génétique Moléculaire et Génomique Médicale, CHU de Rennes, Rennes, France; University of Rennes, CNRS, IGDR, UMR 6290, Rennes, France.
Frances Elmslie, South West Thames Regional Clinical Genetics Service, St George's Hospital, University of London, London, United Kingdom.
Houda Zghal Elloumi, GeneDx, Gaithersburg, MD.
Laurence Faivre, Génétique des Anomalies du Développement, Université de Bourgogne Franche-Comté, UMR1231-Inserm, Dijon, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.
Sarah Fitzgerald-Butt, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University, Indianapolis, IN.
David Geneviève, Medical Genetic Department, Rare Diseases and Personalized Medicine, Montpellier University, Inserm U1183, CHU Montpellier, Montpellier, France.
Jacqueline A. Goos, Department of Plastic and Reconstructive Surgery and Hand Surgery, Dutch Craniofacial Center, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Bioinformatics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Benjamin M. Helm, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University, Indianapolis, IN; Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN.
Usha Kini, Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.
Amaia Lasa-Aranzasti, Department of Clinical and Molecular Genetics, Vall d'Hebron University Hospital and Medicine Genetics Group, Vall d'Hebron Research Institute, Barcelona, Spain.
Gaetan Lesca, Service de Génétique, Hospices Civils de Lyon, Bron, France; Institut NeuroMyoGene, CNRS UMR5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France.
Sally A. Lynch, Department of Clinical Genetics, Children's Health Ireland at Crumlin and Temple Street, Dublin, Ireland.
Irene M. Mathijssen, Department of Plastic and Reconstructive Surgery and Hand Surgery, Dutch Craniofacial Center, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Ruth McGowan, West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Scottish Genomes Partnership, Glasgow, United Kingdom.
Kristin G. Monaghan, GeneDx, Gaithersburg, MD.
Sylvie Odent, CHU Rennes, Service de Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN ITHACA, Hôpital Sud, Rennes, France.
et al
Recommended Citation
de Boer E, Ockeloen CW, Kampen RA, et al. Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein. Genet Med. 2022;24(10):2051-2064. doi:10.1016/j.gim.2022.06.007
Abstract
Purpose: Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants.
Methods: We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments.
Results: We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity.
Conclusion: Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping.
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Affiliations
Advocate Children's Hospital