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.
| Original language | English |
|---|---|
| Pages (from-to) | 2051-2064 |
| Number of pages | 14 |
| Journal | Genetics in Medicine |
| Volume | 24 |
| Issue number | 10 |
| Early online date | 14 Jul 2022 |
| DOIs | |
| Publication status | Published - 4 Oct 2022 |
Bibliographical note
Funding Information:In addition, the collaborations in this study were facilitated by ERN ITHACA, one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States, cofunded by European Commission. The aims of this study contribute to the Solve-RD project (E.d.B., A.S.D.P., L.F., C.G., T.K., A.V., L.E.L.M.V.), which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement number 779257.
Funding Information:
We are very grateful to all individuals and their families for their participation in this study. This work was financially supported by Aspasia grants of the Dutch Research Council (015.014.036 to T.K. and 015.014.066 to L.E.L.M.V.), Netherlands Organization for Health Research and Development (91718310 to T.K.), and the Max Planck Society (M.M.K.W. S.E.F.). Individual 4 was sequenced at the Scottish Genomes Partnership. The Scottish Genomes Partnership was funded by the Chief Scientist Office of the Scottish Government Health Directorates (SGP/1) and the Medical Research Council Whole Genome Sequencing for Health and Wealth Initiative (MC/PC/15080). The Deciphering Developmental Disorders study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). This study makes use of Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (https://www.deciphergenomics.org/), which is funded by Wellcome. See Deciphering Developmental Disorders study8 or https://www.ddduk.org/access.html for full acknowledgment. In addition, the collaborations in this study were facilitated by ERN ITHACA, one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States, cofunded by European Commission. The aims of this study contribute to the Solve-RD project (E.d.B. A.S.D.P. L.F. C.G. T.K. A.V. L.E.L.M.V.), which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement number 779257. Conceptualization: C.W.O. M.M.K.W. T.K.; Data Curation: E.d.B. C.W.O. D.R. T.A. R.B. M.B.-H. B.A. N.C. A.-S.D.-P. O.D. C.D. F.E. H.Z.E. L.F. S.F.B. D.G. J.A.C.G. B.M.H. U.K. A.L.-A. G.L. S.A.L. I.M.J.M. R.M.G. K.G.M. S.O. R.P. A.P. J.v.R. G.W.E.S. E.S. A.S. P.J.v.d.S. A.P.A.S. S.M.A.S. I.V. E.V.-D. A.V. S.M.W. M.W. K.J.L. T.K.; Formal Analysis: E.d.B. M.M.K.W. C.W.O. L.E.L.M.V. S.E.F. T.K.; Investigation: R.A.K. E.d.B, M.M.K.W. C.W.O. T.K.; Software: L.L. A.J.M.D. J.E.H. C.G.; Writing-original draft: E.d.B. M.M.K.W. C.W.O. T.K.; Supervision: C.W.O. M.M.K.W. T.K.; All authors contributed to the final version of the manuscript. We obtained informed consent to publish unidentifiable data for all individuals reported in this study. Specific consent was obtained for publication of clinical photographs. Consent procedures were in accordance with the Declaration of Helsinki and local ethical guidelines of the participating centers. The institutional review board 'Commissie Mensgebonden Onderzoek Regio Arnhem-Nijmegen' approved this study under number 2011/188 and 2022-13611. Number 2011/188 refers to performing diagnostic exome sequencing. Discovery of novel syndromes and description of clinical cohorts from this series can be taken as such. Number 2022-13611 refers to publishing Human Phenotype Ontology data for individuals in Biobank Genetics and Rare Diseases and Biobank Intellectual Disability of the Radboudumc. All the appropriate institutional forms have been archived locally.
Funding Information:
We are very grateful to all individuals and their families for their participation in this study. This work was financially supported by Aspasia grants of the Dutch Research Council (015.014.036 to T.K. and 015.014.066 to L.E.L.M.V.), Netherlands Organization for Health Research and Development (91718310 to T.K.), and the Max Planck Society (M.M.K.W., S.E.F.). Individual 4 was sequenced at the Scottish Genomes Partnership. The Scottish Genomes Partnership was funded by the Chief Scientist Office of the Scottish Government Health Directorates (SGP/1) and the Medical Research Council Whole Genome Sequencing for Health and Wealth Initiative (MC/PC/15080). The Deciphering Developmental Disorders study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). This study makes use of Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources ( https://www.deciphergenomics.org/ ), which is funded by Wellcome . See Deciphering Developmental Disorders study 8 or https://www.ddduk.org/access.html for full acknowledgment.
Publisher Copyright:
© 2022 The Authors
Keywords
- ANKRD11
- Genotype–phenotype study
- KBG syndrome
- Missense variants
- Neurodevelopmental disorders