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

Elke de Boer, Charlotte W. Ockeloen*, Rosalie A. Kampen, Juliet E. Hampstead, Alexander J.M. Dingemans, Dmitrijs Rots, Lukas Lütje, Tazeen Ashraf, Rachel Baker, Mouna Barat-Houari, Brad Angle, Nicolas Chatron, Anne Sophie Denommé-Pichon, Orrin Devinsky, Christèle Dubourg, Frances Elmslie, Houda Zghal Elloumi, Laurence Faivre, Sarah Fitzgerald-Butt, David GenevièveJacqueline A.C. Goos, Benjamin M. Helm, Usha Kini, Amaia Lasa-Aranzasti, Gaetan Lesca, Sally A. Lynch, Irene M.J. Mathijssen, Ruth McGowan, Kristin G. Monaghan, Sylvie Odent, Rolph Pfundt, Audrey Putoux, Jeroen van Reeuwijk, Gijs W.E. Santen, Erina Sasaki, Arthur Sorlin, Peter J. van der Spek, Alexander P.A. Stegmann, Sigrid M.A. Swagemakers, Irene Valenzuela, Eléonore Viora-Dupont, Antonio Vitobello, Stephanie M. Ware, Mathys Wéber, Christian Gilissen, Karen J. Low, Simon E. Fisher, Lisenka E.L.M. Vissers, Maggie M.K. Wong, Tjitske Kleefstra

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)2051-2064
Number of pages14
JournalGenetics in Medicine
Issue number10
Publication statusPublished - 1 Oct 2022

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