de Boer Elke, Ockeloen Charlotte W, Kampen Rosalie A, Hampstead Juliet E, Dingemans Alexander J M, Rots Dmitrijs, Lütje Lukas, Ashraf Tazeen, Baker Rachel, Barat-Houari Mouna, Angle Brad, Chatron Nicolas, Denommé-Pichon Anne-Sophie, Devinsky Orrin, Dubourg Christèle, Elmslie Frances, Elloumi Houda Zghal, Faivre Laurence, Fitzgerald-Butt Sarah, Geneviève David, Goos Jacqueline A C, Helm Benjamin M, Kini Usha, Lasa-Aranzasti Amaia, Lesca Gaetan, Lynch Sally A, Mathijssen Irene M J, McGowan Ruth, Monaghan Kristin G, Odent Sylvie, Pfundt Rolph, Putoux Audrey, van Reeuwijk Jeroen, Santen Gijs W E, Sasaki Erina, Sorlin Arthur, van der Spek Peter J, Stegmann Alexander P A, Swagemakers Sigrid M A, Valenzuela Irene, Viora-Dupont Eléonore, Vitobello Antonio, Ware Stephanie M, Wéber Mathys, Gilissen Christian, Low Karen J, Fisher Simon E, Vissers Lisenka E L M, Wong Maggie M K, Kleefstra Tjitske
Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands.
Genet Med. 2022 Oct;24(10):2051-2064. doi: 10.1016/j.gim.2022.06.007. Epub 2022 Jul 14.
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.
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.
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.
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.
尽管ANKRD11单倍剂量不足是神经发育障碍最常见的遗传原因之一，但罕见的ANKRD11错义变异的作用仍不清楚。我们对ANKRD11错义变异的临床、分子和功能谱进行了表征。
我们收集了携带ANKRD11错义变异个体的临床信息，并评估其与KBG综合征的表型匹配情况。我们通过计算机分析和基于细胞的实验评估变异的致病性。
我们在29名个体中鉴定出20种独特的、大多为新发的ANKRD11错义变异，这些个体表现出与由ANKRD11蛋白截短变异或16q24.3微缺失引起的KBG综合征相似的综合征性神经发育障碍。错义变异显著聚集在ANKRD11 C末端的抑制域2中。在10个经过功能研究的错义变异中，6个降低了ANKRD11的稳定性。一个变异导致蛋白酶体降解减少和ANKRD11转录活性丧失。
我们的研究表明，致病性杂合ANKRD11错义变异可导致临床上可识别的KBG综合征。转录抑制能力破坏和蛋白质稳定性降低各自独立导致ANKRD11功能丧失，与单倍剂量不足一致。这突出了ANKRD11错义变异的诊断相关性，但也带来了诊断挑战，因为与KBG相关的表型可能较轻，且越来越多地观察到遗传性致病性ANKRD11（错义）变异，需要严格的变异分类和仔细的表型分析。
