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., 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.
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.