Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein - Université de Rennes Accéder directement au contenu
Article Dans Une Revue Genetics in Medicine Année : 2022

Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein

1 Radboud University [Nijmegen]
2 Max Planck Institute for Psycholinguistics
3 Radboud Institute for Molecular Life Sciences [Nijmegen, the Netherlands]
4 Guy's and St Thomas' NHS Foundation Trust
5 GOSHC - Great Ormond Street Hospital for Children NHS Foundation Trust [London, UK]
6 Advocate Hope Children's Hospital,
7 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
8 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
9 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
10 INMG-AR - Institut NeuroMyoGène - Appui à la recherche
11 UF6254 - Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon)
12 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
13 NYU Grossman School of Medicine - New York University School of Medicine
14 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
15 IGDR - Institut de Génétique et Développement de Rennes
16 St George’s University Hospitals
17 GeneDx [Gaithersburg, MD, USA]
18 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
19 FHU TRANSLAD (CHU de Dijon)
20 University of Indianapolis
21 Erasmus MC - Erasmus University Medical Center [Rotterdam]
22 Indiana University School of Medicine
23 Oxford University Hospitals NHS Trust
24 VHIR - Vall d’Hebron Research Institute
25 HCL - Hospices Civils de Lyon
26 Children's Health Ireland at Temple Street
27 Queen Elizabeth University Hospital (Glasgow)
28 Radboud University Medical Center [Nijmegen]
29 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
30 LUMC - Leiden University Medical Center
31 MUMC - Maastricht University Medical Centre
32 University Hospitals Bristol
33 Department of Human Genetics [Nijmegen]
34 Donders Institute for Brain, Cognition and Behaviour
Elke de Boer
Orrin Devinsky
Frances Elmslie
Rolph Pfundt
  • Fonction : Auteur
  • PersonId : 889767
Simon E Fisher
Maggie M.K. Wong
  • Fonction : Auteur

Résumé

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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Origine : Publication financée par une institution
Commentaire : This latest version inclues correction the revised Figure 3 (correction https://doi.org/10.1016/j.gim.2023.100962)

Dates et versions

hal-03790568 , version 1 (20-01-2023)
hal-03790568 , version 2 (23-11-2023)

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Elke de Boer, Charlotte Ockeloen, Rosalie Kampen, Juliet Hampstead, Alexander Dingemans, et al.. Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein. Genetics in Medicine, 2022, 24 (10), pp.2051-2064. ⟨10.1016/j.gim.2022.06.007⟩. ⟨hal-03790568v2⟩
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