期刊
GENETICS IN MEDICINE
卷 24, 期 10, 页码 2051-2064出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.gim.2022.06.007
关键词
ANKRD11; Genotype-phenotype study; KBG syndrome; Missense variants; Neurodevelopmental disorders
资金
- Aspasia grants of the Dutch Research Council [015.014.036, 015.014.066]
- Netherlands Organization for Health Research and Development [91718310]
- Max Planck Society
- Chief Scientist Office of the Scottish Government Health Directorates (SGP/1)
- Medical Research Council Whole Genome Sequencing for Health and Wealth Initiative [MC/PC/15080]
- Health Innovation Challenge Fund [HICF-1009-003]
- Wellcome
- European Union's Horizon 2020 research and innovation programme [779257]
This study indicates that pathogenic ANKRD11 missense variants cause KBG syndrome with distinct features. Disrupted transrepression capacity and reduced protein stability both result in the loss of ANKRD11 function.
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. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据