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

de Boer, E; Ockeloen, CW; Kampen, RA; Hampstead, JE; Dingemans, AJM; Rots, D; Lütje, L; Ashraf, T; Baker, R; Barat-Houari, M; et al. de Boer, E; Ockeloen, CW; Kampen, RA; Hampstead, JE; Dingemans, AJM; Rots, D; Lütje, L; Ashraf, T; Baker, R; Barat-Houari, M; Angle, B; Chatron, N; Denommé-Pichon, A-S; Devinsky, O; Dubourg, C; Elmslie, F; Elloumi, HZ; Faivre, L; Fitzgerald-Butt, S; Geneviève, D; Goos, JAC; Helm, BM; Kini, U; Lasa-Aranzasti, A; Lesca, G; Lynch, SA; Mathijssen, IMJ; McGowan, R; Monaghan, KG; Odent, S; Pfundt, R; Putoux, A; van Reeuwijk, J; Santen, GWE; Sasaki, E; Sorlin, A; van der Spek, PJ; Stegmann, APA; Swagemakers, SMA; Valenzuela, I; Viora-Dupont, E; Vitobello, A; Ware, SM; Wéber, M; Gilissen, C; Low, KJ; Fisher, SE; Vissers, LELM; Wong, MMK; Kleefstra, T (2022) Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein. Genet Med, 24 (10). pp. 2051-2064. ISSN 1530-0366 https://doi.org/10.1016/j.gim.2022.06.007
SGUL Authors: Elmslie, Frances

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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.

Item Type: Article
Additional Information: Correction available at https://doi.org/10.1016/j.gim.2023.100962 © 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: ANKRD11, Genotype–phenotype study, KBG syndrome, Missense variants, Neurodevelopmental disorders, Abnormalities, Multiple, Bone Diseases, Developmental, Chromosome Deletion, Facies, Humans, Intellectual Disability, Mutation, Missense, Phenotype, Proteasome Endopeptidase Complex, Repressor Proteins, Tooth Abnormalities, Transcription Factors, Humans, Bone Diseases, Developmental, Tooth Abnormalities, Abnormalities, Multiple, Chromosome Deletion, Facies, Proteasome Endopeptidase Complex, Transcription Factors, Repressor Proteins, Phenotype, Mutation, Missense, Intellectual Disability, ANKRD11, Genotype-phenotype study, KBG syndrome, Missense variants, Neurodevelopmental disorders, 0604 Genetics, 1103 Clinical Sciences, Genetics & Heredity
Journal or Publication Title: Genet Med
ISSN: 1530-0366
Language: eng
Dates:
DateEvent
4 October 2022Published
14 July 2022Published Online
21 June 2022Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
015.014.036Dutch Research CouncilUNSPECIFIED
015.014.066Dutch Research CouncilUNSPECIFIED
91718310Netherlands Organization for Health Research and DevelopmentUNSPECIFIED
SGP/1Chief Scientist Officehttp://dx.doi.org/10.13039/501100000589
MC/PC/15080Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
HICF-1009-003Health Innovation Challenge FundUNSPECIFIED
779257Horizon 2020http://dx.doi.org/10.13039/501100007601
PubMed ID: 35833929
Web of Science ID: WOS:000879580900007
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/115087
Publisher's version: https://doi.org/10.1016/j.gim.2022.06.007

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