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 Geneviève; Jacqueline 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

doi:10.1016/j.gim.2022.06.007

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 journal › Article › Academic › peer-review

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	13 Jul 2022
DOIs	https://doi.org/10.1016/j.gim.2022.06.007
Publication status	Published - Oct 2022

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de Boer, E., Ockeloen, C. W., Kampen, R. A., Hampstead, J. E., Dingemans, A. J. M., 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, H. Z., Faivre, L., Fitzgerald-Butt, S., ... Kleefstra, T. (2022). Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein. Genetics in Medicine, 24(10), 2051-2064. https://doi.org/10.1016/j.gim.2022.06.007

@article{df354f9f55e446e68c75940a36f43743,

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

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.",

author = "{de Boer}, Elke and Ockeloen, {Charlotte W} and Kampen, {Rosalie A} and Hampstead, {Juliet E} and Dingemans, {Alexander J M} and Dmitrijs Rots and Lukas L{\"u}tje and Tazeen Ashraf and Rachel Baker and Mouna Barat-Houari and Brad Angle and Nicolas Chatron and Anne-Sophie Denomm{\'e}-Pichon and Orrin Devinsky and Christ{\`e}le Dubourg and Frances Elmslie and Elloumi, {Houda Zghal} and Laurence Faivre and Sarah Fitzgerald-Butt and David Genevi{\`e}ve and Goos, {Jacqueline A C} and Helm, {Benjamin M} and Usha Kini and Amaia Lasa-Aranzasti and Gaetan Lesca and Lynch, {Sally A} and Mathijssen, {Irene M J} and Ruth McGowan and Monaghan, {Kristin G} and Sylvie Odent and Rolph Pfundt and Audrey Putoux and {van Reeuwijk}, Jeroen and Santen, {Gijs W E} and Erina Sasaki and Arthur Sorlin and {van der Spek}, {Peter J} and Stegmann, {Alexander P A} and Swagemakers, {Sigrid M A} and Irene Valenzuela and El{\'e}onore Viora-Dupont and Antonio Vitobello and Ware, {Stephanie M} and Mathys W{\'e}ber and Christian Gilissen and Low, {Karen J} and Fisher, {Simon E} and Vissers, {Lisenka E L M} and Wong, {Maggie M K} and Tjitske Kleefstra",

year = "2022",

month = oct,

doi = "10.1016/j.gim.2022.06.007",

language = "English",

volume = "24",

pages = "2051--2064",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Nature Publishing Group",

number = "10",

}

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 2022, 'Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein', Genetics in Medicine, vol. 24, no. 10, pp. 2051-2064. https://doi.org/10.1016/j.gim.2022.06.007

TY - JOUR

T1 - Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein

AU - de Boer, Elke

AU - Ockeloen, Charlotte W

AU - Kampen, Rosalie A

AU - Hampstead, Juliet E

AU - Dingemans, Alexander J M

AU - Rots, Dmitrijs

AU - Lütje, Lukas

AU - Ashraf, Tazeen

AU - Baker, Rachel

AU - Barat-Houari, Mouna

AU - Angle, Brad

AU - Chatron, Nicolas

AU - Denommé-Pichon, Anne-Sophie

AU - Devinsky, Orrin

AU - Dubourg, Christèle

AU - Elmslie, Frances

AU - Elloumi, Houda Zghal

AU - Faivre, Laurence

AU - Fitzgerald-Butt, Sarah

AU - Geneviève, David

AU - Goos, Jacqueline A C

AU - Helm, Benjamin M

AU - Kini, Usha

AU - Lasa-Aranzasti, Amaia

AU - Lesca, Gaetan

AU - Lynch, Sally A

AU - Mathijssen, Irene M J

AU - McGowan, Ruth

AU - Monaghan, Kristin G

AU - Odent, Sylvie

AU - Pfundt, Rolph

AU - Putoux, Audrey

AU - van Reeuwijk, Jeroen

AU - Santen, Gijs W E

AU - Sasaki, Erina

AU - Sorlin, Arthur

AU - van der Spek, Peter J

AU - Stegmann, Alexander P A

AU - Swagemakers, Sigrid M A

AU - Valenzuela, Irene

AU - Viora-Dupont, Eléonore

AU - Vitobello, Antonio

AU - Ware, Stephanie M

AU - Wéber, Mathys

AU - Gilissen, Christian

AU - Low, Karen J

AU - Fisher, Simon E

AU - Vissers, Lisenka E L M

AU - Wong, Maggie M K

AU - Kleefstra, Tjitske

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

U2 - 10.1016/j.gim.2022.06.007

DO - 10.1016/j.gim.2022.06.007

M3 - Article

C2 - 35833929

SN - 1098-3600

VL - 24

SP - 2051

EP - 2064

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 10

ER -

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

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